CN102958914B - 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators - Google Patents

1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators Download PDF

Info

Publication number
CN102958914B
CN102958914B CN201180030390.1A CN201180030390A CN102958914B CN 102958914 B CN102958914 B CN 102958914B CN 201180030390 A CN201180030390 A CN 201180030390A CN 102958914 B CN102958914 B CN 102958914B
Authority
CN
China
Prior art keywords
isoquinoline
chloro
phenyl
fluoro
dihydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201180030390.1A
Other languages
Chinese (zh)
Other versions
CN102958914A (en
Inventor
汗默德·艾萨维
克里斯托弗·博斯
朱利安·波蒂埃
西尔维娅·理查德-比尔德斯滕
菲利普·里奇
罗曼·西格里斯特
海因茨·弗雷茨
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aidu West Pharmaceutical Co Ltd
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of CN102958914A publication Critical patent/CN102958914A/en
Application granted granted Critical
Publication of CN102958914B publication Critical patent/CN102958914B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Otolaryngology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

The present invention relates to 1-phenyl-substituted heterocyclyl derivatives of the formula (I), wherein X, Y, Z, n, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7> and R<10> are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

Description

The Hete rocyclic derivatives that 1-phenyl replaces and the purposes as prostaglandin D 2 receptor conditioning agent thereof
Technical field
The present invention relates to formula (I) 1-phenyl replace Hete rocyclic derivatives and as prostaglandin receptor conditioning agent, particularly as PGD 2the purposes of acceptor (" DP acceptor ") conditioning agent in the various prostaglandin mediated disease for the treatment of and illness, relates to medical composition containing these compounds and preparation method thereof.In detail, these derivatives can be used for the treatment of chronic and acute allergic/Immunological diseases/illness separately or with medical composition form, such as asthma, allergic asthma, addicted to Yihong blood cell asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergies, drug allergy, allergic sinusitis, allergic nephritis, anaphylaxis conjunctivitis, atopic dermatitis, bronchial asthma, food anaphylaxis, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory enteropathy and rheumatoid arthritis, addicted to Yihong blood cell relative disease, comprise polyangitis, as Xie Ge-Si Tuosi syndrome (Churg-Strauss syndrome), Wei Genashi granuloma (Wegener's granulomatosis), microscopic Polyangiitis (and the microscopic Polyangiitis of organ specificity), waits group addicted to her erythrocytosis, as addicted to Yihong blood cell pneumonia, addicted to Yihong blood cell esophagitis, reflux esophagitis, addicted to Yihong blood cell endocarditis (Lv Foleshi endocarditis (Loeffler'sendocarditis)), addicted to her erythrocytosis-myalgia syndrome, addicted to Yihong blood cell fascitis, addicted to Yihong blood cell pustule type folliculitis (too Teng Shi disease (Ofuji ' s disease)), addicted to Yihong blood cell ulcer, ALH is concurrent addicted to her erythrocytosis (ALHE), addicted to Yihong blood cell cellulitis (Wei Ersi syndrome (Wells syndrome)), chronic addicted to Yihong blood cell leukemia and DRESS syndrome (drug eruption is concurrent addicted to her erythrocytosis and systemic symptoms), and basophilia blood cell relative disease, comprise Basophilic leukemia and basophilia leukocytosis disease.
Background technology
As in allergic condition to the reaction that anaphylactogen exposes to the open air, the activated and release of mastocyte is as histamine, the plain A2 (TxA2) of blood coagulation fat, cysteamine acyl group leukotriene (CysLT) and PGD 2(PGD 2) medium.These media acceptor interaction out of the ordinary with it and cause such as following physiological action: vascular permeability increase, oedema, itch, nasal congestion and pulmonary congestion, bronchoconstriction and mucilage secretion.For example, vascular permeability increase makes addicted to therefore amplifying anaphylaxis in Yihong blood cell white cell and basophilia white cell excessive infiltration tissue.
The Current therapeutic of anaphylactic disease comprises these interactional medicaments of capable of blocking or other interruption, such as antihistaminic (histamine H 1 receptor's antagonist), LTRA, receptor,β agonist and reflunomide.Generally speaking, the limited efficacy for the treatment of with antihistaminic and leukotriene antagonist, and life-time service reflunomide is usually relevant to undesirable side effect.
PGD 2for known action is in two kinds of G-protein matter coupled receptors, that is PGD 2the agonist of acceptor DP1 and recent differentiated CRTH2 (finding expression in the chemoattractant receptor homolgous molecule on Th2 cell) acceptor (being also called " DP2 acceptor ").
Think high PGD 2content to cause in the anaphylactic disease as such as allergic rhinitis, allergic asthma, anaphylaxis conjunctivitis, atopic dermatitis and similar disease thereof the inflammation that observes.Therefore, think block PGD 2be the useful therapeutic strategy for the treatment of these diseases with the interaction of its acceptor.
GB 2388540 discloses TxA2 acceptor (being also called " TP acceptor ") antagonist Ramatroban (ramatroban) ((the 3R)-3-(4-fluorobenzene-sulfonamido)-1 in addition CRTH2 to antagonistic activity, 2,3,4-tetrahydro carbazole-9-propionic acid) for the purposes of the Prevention and Curation such as anaphylactic disease of asthma, allergic rhinitis or anaphylaxis conjunctivitis.The people such as T.Ishizuka, Cardiovascular Drug Rev.2004, describes the effect of Ramatroban to late phase inflammation in 22 (2), 71-90.In addition, reported the oral bio operability of Ramatroban and in vitro suppressed PGD 2the ability (Journal ofPharmacology and Experimental Therapeutics, 305 (1), 347-352 page (2003)) addicted to the migration of Yihong blood cell of induction.
WO 03/097598 and WO 03/097042 discloses the Ramatroban analogue with CRTH2 antagonistic activity.The people such as Ulven, J.Med.Chem.2005,48 (4), 897-900 disclose other Ramatroban analogues.
CRTH2 antagonist containing phenoxy group-acetate moiety is such as described in WO 05/105727, WO06/056752, WO 07/037187 and WO 07/052023.
Summary of the invention
1) Hete rocyclic derivatives that the 1-phenyl that the present invention relates to formula (I) replaces,
Wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O or S;
N represents 0 or 1;
R 1represent
(C 4-C 6) alkyl;
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted;
(C 2-C 4) thiazolinyl, its aryl through being optionally substituted is monosubstituted;
(C 2-C 4) alkynyl, its aryl through being optionally substituted is monosubstituted;
(C 3-C 6) cycloalkyl, it is through (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) alkoxyl group is monosubstituted, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted;
The aryl be optionally substituted; Or
10 yuan of unsaturated loop systems of part;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, (C 1-C 4) alkyl sulphonyl, benzenesulfonyl or (C 1-C 4) alkyl sulfonyl amino;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxyl group, halogen, (C 1-C 4) alkyl sulphonyl, the aryl be optionally substituted or the heteroaryl be optionally substituted;
R 5represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group ,-CONH 2, the optionally aryl, the heteroaryl be optionally the substituted, (C that are substituted 1-C 4) alkyl sulphonyl, benzenesulfonyl or dimethylamino-alkylsulfonyl; And
R 6represent hydrogen or halogen; Or
R 5and R 6form methylene-dioxy together;
R 7represent hydrogen or methyl;
R 8represent hydrogen or methyl;
R 9represent the aryl, the aryl sulfonyl be optionally substituted or the heteroarylsulfonyl be optionally substituted that are optionally substituted; And
R 10represent-C (O) OH ,-C (O) NH-CN ,-C (O) NH-OH ,-C (O) NH-S (O) 2cF 3or the heteroaryl be optionally substituted;
If its restricted condition represents-NH-or a key for X, then R 1aryl not for being optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
Embodiment 1) formula (I) compound can contain one or more Stereocenter or asymmetric center, such as one or more unsymmetrical carbon.Unless otherwise instructed, otherwise the substituting group at double bond place can be (Z)-or (E)-configuration.Therefore formula I can the mixture of steric isomer or preferably Pure stereoisomeric forms existence.The mixture of steric isomer can be separated in the manner known to persons skilled in the art.
Following paragraph provides the definition of the various chemical parts of the compounds of this invention, and definition provides wider or narrower definition unless otherwise specifically indicated, otherwise is intended to give a definition as one man be applied to entire description and claim.
In present application for patent, variable connecting key can be used for substituting group or group.In the case, mean any carbon atom that substituting group or group are connected to the loop systems that variable connecting key is introduced, its restricted condition is that this carbon atom is not yet through specific replacement.For example, formula (I) contains following three formulas:
For avoiding any doubt, n represents that the formula I of 0 is by formula I iSOrepresent; And n represents that the formula I of 1 is by formula I tETrepresent:
The term " alkyl " be used alone or in combination refers to straight chain containing 1 to 6 carbon atom or branched-chain alkyl.Term " (C x-C y) alkyl " (x and y respectively for integer) refer to alkyl as previously defined containing x to y carbon atom.For example, (C 1-C 4) alkyl contains 1 to 4 carbon atom.(C 1-C 4) representative example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.(C 4-C 6) representative example of alkyl comprises normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, penta-1-base, penta-2-base, penta-3-base, 2-methyl-Ding-1-base, 3-methyl-Ding-1-base, 2-methyl-Ding-2-base, 3 methyl-Ding-2-bases, 2,2-dimethyl-propyl-1-base and isohexyl.As clearly defined, alkyl can be unsubstituted or be substituted.
If " R 1" expression " (C 4-C 6) alkyl ", then this term means (C as hereinbefore defined 4-C 6) alkyl.The example of these groups is normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, penta-1-base, penta-2-base, penta-3-base, 2-methyl-Ding-1-base, 3-methyl-Ding-1-base, 2-methyl-Ding-2-base, 3-methyl-Ding-2-base, 2,2-dimethyl-propyl-1-base and isohexyl.Be preferably normal-butyl, isobutyl-, the tertiary butyl, penta-1-base, 2-methyl-Ding-1-base, 3-methyl-Ding-1-base and 2,2-dimethyl-propyl-1-base, be more preferably normal-butyl, isobutyl-, the tertiary butyl and 2,2-dimethyl-propyl-1-base, and most preferably be normal-butyl, isobutyl-and 2,2-dimethyl-propyl-1-base.
If " R 1" represent through mono-substituted (C 1-C 4) alkyl, then this term " (C 1-C 4) alkyl " mean (C as hereinbefore defined 1-C 4) alkyl.The example of these groups is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably methyl, ethyl and n-propyl; Most preferably be methyl and ethyl.These (C 1-C 4) alkyl is through following monosubstituted: (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9(and the aryl especially through being optionally substituted, the heteroaryl be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or the aryl-(C be optionally substituted 1-C 2) alkoxyl group is monosubstituted).
If " R 1" expression " warp (C 1-C 4) the monosubstituted or dibasic (C of alkyl 3-C 6) cycloalkyl ", then this term " (C 1-C 4) alkyl " mean (C as hereinbefore defined 1-C 4) alkyl.The example of these groups is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably methyl, ethyl and sec.-propyl and most preferably be methyl.
If " R 2" expression " (C 1-C 4) alkyl ", then this term means (C as hereinbefore defined 1-C 4) alkyl.The example of these groups is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably methyl.
If " R 5" expression " (C 1-C 4) alkyl ", then this term means (C as hereinbefore defined 1-C 4) alkyl.The example of these groups is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably methyl and sec.-propyl; Most preferably be methyl.
If " (C 1-C 4) alkyl " be aryl, heteroaryl, heterocyclic radical, aryloxy, heteroaryl oxygen base, aryl-(C 1-C 2) alkoxyl group, heteroaryl-(C 1-C 2) substituting group of alkoxyl group, Heteroarylthio, aryl sulfonyl or heteroarylsulfonyl, then this term " (C 1-C 4) alkyl " mean (C as hereinbefore defined 1-C 4) alkyl.The example of these groups is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably methyl and ethyl; Most preferably be methyl.
As term " (C used in Y 1-C 4) alkane two base (alkandiyl, alkylidene group or alkylene) " refer to containing 1 to 4 carbon atom and be connected to Sauerstoffatom and such as formula the R described in (I) 10carbochain.Two residues out of the ordinary can be connected to the identical or different carbon atom of alkane two base.(C 1-C 4) preferred embodiment of alkane two base is methylene radical (methandiyl, first two base), second-1,1-bis-base, second-1,2-bis-base, the third-1,3-bis-base and fourth-Isosorbide-5-Nitrae-two base.Be more preferably methylene radical and second-1,1-bis-base.Most preferably be methylene radical.
The term " thiazolinyl " be used alone or in combination refers to straight chain containing 2 to 4 carbon atoms or branched chain alkene groups.Term " (C x-C y) thiazolinyl " (x and y respectively for integer) refer to thiazolinyl as previously defined containing x to y carbon atom.For example, (C 2-C 4) thiazolinyl contains 2 to 4 carbon atoms.(C 2-C 4) representative example of thiazolinyl comprises vinyl, propenyl, 2-methyl-propenyl and butenyl.Be preferably vinyl.(C 2-C 4) aryl of thiazolinyl through being optionally substituted be monosubstituted.
The term " alkynyl " be used alone or in combination refers to straight chain containing 2 to 4 carbon atoms or branched chain alkyne groups.Term " (C x-C y) alkynyl " (x and y respectively for integer) refer to alkynyl as previously defined containing x to y carbon atom.For example, (C 2-C 4) alkynyl contains 2 to 4 carbon atoms.(C 2-C 4) representative example of alkynyl comprises ethynyl, proyl and butynyl.Be preferably ethynyl.(C 2-C 4) aryl of alkynyl through being optionally substituted be monosubstituted.
The term " alkoxyl group " be used alone or in combination refers to allcyl-O-groups, and wherein this alkyl is as previously defined.Term " (C x-C y) alkoxyl group " (x and y respectively for integer) refer to alkoxyl group as previously defined containing x to y carbon atom.For example, (C 1-C 4) alkoxyl group contains 1 to 4 carbon atom.The representative example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
If " R 1" expression " warp (C 1-C 4) mono-substituted (C of alkoxyl group 1-C 4) alkyl ", then this term " (C 1-C 4) alkoxyl group " mean (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Be preferably methoxyl group and isobutoxy.Most preferably be methoxyl group.
If " R 1" expression " warp (C 1-C 4) mono-substituted (C of alkoxyl group 3-C 6) cycloalkyl ", then this term " (C 1-C 4) alkoxyl group " mean (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Be preferably methoxyl group and oxyethyl group.Most preferably be oxyethyl group.
If " R 2" expression " (C 1-C 4) alkoxyl group ", then this term means (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Most preferably be methoxyl group.
If " R 3" expression " (C 1-C 4) alkoxyl group ", then this term means (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Most preferably be methoxyl group.
If " R 4" expression " (C 1-C 4) alkoxyl group ", then this term means (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Most preferably be methoxyl group.
If " R 5" expression " (C 1-C 4) alkoxyl group ", then this term means (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Most preferably be methoxyl group.
If " (C 1-C 4) alkoxyl group " be aryl, heteroaryl, heterocyclic radical, aryloxy, heteroaryl oxygen base, aryl-(C 1-C 2) alkoxyl group, heteroaryl-(C 1-C 2) substituting group of alkoxyl group, Heteroarylthio, aryl sulfonyl or heteroarylsulfonyl, then this term " (C 1-C 4) alkoxyl group " mean (C as hereinbefore defined 1-C 4) alkoxyl group.The example of these groups is methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Most preferably be methoxyl group.
Term " aryl-(C 1-C 2) alkoxyl group " and refer to a hydrogen atom as hereafter define aryl displacement (C as hereinbefore defined 1-C 2) alkoxyl group.Aryl-(C 1-C 2) example of alkoxyl group is aryl-methoxyl group, 1-aryl-oxyethyl group and 2-aryl-oxyethyl group.Most preferably be aryl-methoxyl group.
Term " heteroaryl-(C 1-C 2) alkoxyl group " and refer to a hydrogen atom as hereafter define heteroaryl displacement (C as hereinbefore defined 1-C 2) alkoxyl group.Heteroaryl-(C 1-C 2) example of alkoxyl group is heteroaryl-methoxyl group, 1-heteroaryl-oxyethyl group and 2-heteroaryl-oxyethyl group.Most preferably be heteroaryl-methoxyl group.
The term " (C be used alone or in combination 1-C 4) alkyl sulphonyl " refer to alkyl-S (O) 2-group, wherein this alkyl is as previously defined, and it is the rest part being connected to molecule via sulphur atom.Term " (C x-C y) alkyl sulphonyl " (x and y respectively for integer) refer to alkyl sulphonyl as previously defined containing x to y carbon atom.For example, (C 1-C 4) alkyl sulphonyl contains 1 to 4 carbon atom.The representative example of alkyl sulphonyl comprises methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, isopropylsulfonyl, positive fourth alkylsulfonyl, isobutyl alkylsulfonyl, Zhong Ding alkylsulfonyl and tertiary fourth alkylsulfonyl.
If " R 2" expression " (C 1-C 4) alkyl sulphonyl ", then this term means (C as hereinbefore defined 1-C 4) alkyl sulphonyl.The example of these groups is methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, isopropylsulfonyl, positive fourth alkylsulfonyl, isobutyl alkylsulfonyl, Zhong Ding alkylsulfonyl and tertiary fourth alkylsulfonyl.Be preferably methylsulfonyl and ethylsulfonyl; Most preferably be methylsulfonyl.
If " R 4" expression " (C 1-C 4) alkyl sulphonyl ", then this term means (C as hereinbefore defined 1-C 4) alkyl sulphonyl.The example of these groups is methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, isopropylsulfonyl, positive fourth alkylsulfonyl, isobutyl alkylsulfonyl, Zhong Ding alkylsulfonyl and tertiary fourth alkylsulfonyl.Be preferably methylsulfonyl and ethylsulfonyl; Most preferably be ethylsulfonyl.
If " R 5" expression " (C 1-C 4) alkyl sulphonyl ", then this term means (C as hereinbefore defined 1-C 4) alkyl sulphonyl.The example of these groups is methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, isopropylsulfonyl, positive fourth alkylsulfonyl, isobutyl alkylsulfonyl, Zhong Ding alkylsulfonyl and tertiary fourth alkylsulfonyl.Be preferably methylsulfonyl and ethylsulfonyl; Most preferably be ethylsulfonyl.
If " (C 1-C 4) alkyl sulphonyl " be aryl, heteroaryl, heterocyclic radical, aryloxy, heteroaryl oxygen base, aryl-(C 1-C 2) alkoxyl group, heteroaryl-(C 1-C 2) substituting group of alkoxyl group, Heteroarylthio, aryl sulfonyl or heteroarylsulfonyl, then this term " (C 1-C 4) alkyl sulphonyl " mean (C as hereinbefore defined 1-C 4) alkyl sulphonyl.The example of these groups is methylsulfonyl, ethylsulfonyl, positive third alkylsulfonyl, isopropylsulfonyl, positive fourth alkylsulfonyl, isobutyl alkylsulfonyl, Zhong Ding alkylsulfonyl and tertiary fourth alkylsulfonyl.Be preferably methylsulfonyl.
The term " (C be used alone or in combination 1-C 4) alkyl sulfonyl amino " refer to alkyl-S (O) 2n-group, wherein this alkyl is as previously defined, and it is the rest part being connected to molecule via nitrogen-atoms.Term " (C x-C y) alkyl sulfonyl is amino " (x and y is respectively integer) refer to that the alkyl sulfonyl as previously defined containing x to y carbon atom is amino.For example, (C 1-C 4) alkyl sulfonyl amino is containing 1 to 4 carbon atom.The representative example of alkyl sulfonyl amino comprises methanesulfonamido, ethanesulfonamido, positive third sulfonamido, isopropyl sulfonamido, positive fourth sulfonamido, isobutyl sulfonamido, Zhong Ding sulfonamido and tertiary fourth sulfonamido.Be preferably methanesulfonamido.
The term " cycloalkyl " be used alone or in combination refers to the cycloalkyl containing 3 to 6 carbon atoms.Term " (C x-C y) cycloalkyl " (x and y respectively for integer) refer to cycloalkyl as previously defined containing x to y carbon atom.For example, (C 3-C 6) cycloalkyl contains 3 to 6 carbon atoms.Cycloalkyl containing 5 or 6 carbon atoms can optionally and phenyl ring ring.(C 3-C 6) example of cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetralyl.As clearly defined, cycloalkyl can be unsubstituted or be substituted.
If " R 1" expression " warp (C 3-C 6) mono-substituted (C of cycloalkyl 1-C 4) alkyl ", then this term " (C 3-C 6) cycloalkyl " mean (C as hereinbefore defined 3-C 6) cycloalkyl.The example of these groups is cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetralyl.Be preferably cyclopropyl, indanyl and 1,2,3,4-tetralyl; Most preferably be indanyl (being especially indane-2-base).In another embodiment, cyclopentyl and cyclohexyl is preferably.
If " R 1" expression " (C 3-C 6) cycloalkyl ", then this term means (C as hereinbefore defined 3-C 6) cycloalkyl.The example of these groups is cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl and 1,2,3,4-tetralyl.Be preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Most preferably be cyclopropyl.These (C 3-C 6) cycloalkyl warp (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) monosubstituted or through being optionally substituted the heteroaryl of monosubstituted, through being optionally substituted the aryl of alkoxyl group monosubstituted (and the preferred aryl through being optionally substituted is monosubstituted).
Term " (C x-C y) fluoroalkyl " (x and y respectively for integer) refer to containing x to y carbon atom and the alkyl as previously defined of one or more (and may own) hydrogen atom fluorine displacement.For example, (C 1-C 4) fluoroalkyl contains 1 to 4 carbon atom, wherein 1 to 9 hydrogen atom fluorine displacement.
If " R 2" expression " (C 1-C 4) fluoroalkyl ", then this term means (C as hereinbefore defined 1-C 4) fluoroalkyl.The example of these groups is difluoromethyl, trifluoromethyl, 2,2-bis-fluoro ethyls and 2,2,2-trifluoroethyl.Be preferably trifluoromethyl.
If " R 5" expression " (C 1-C 4) fluoroalkyl ", then this term means (C as hereinbefore defined 1-C 4) fluoroalkyl.The example of these groups is difluoromethyl, trifluoromethyl, 2,2-bis-fluoro ethyls and 2,2,2-trifluoroethyl.Be preferably trifluoromethyl.
If " (C 1-C 4) fluoroalkyl " be aryl, heteroaryl, heterocyclic radical, aryloxy, heteroaryl oxygen base, aryl-(C 1-C 2) alkoxyl group, heteroaryl-(C 1-C 2) substituting group of alkoxyl group, Heteroarylthio, aryl sulfonyl or heteroarylsulfonyl, then this term " (C 1-C 4) fluoroalkyl " mean (C as hereinbefore defined 1-C 4) fluoroalkyl.The example of these groups is difluoromethyl, trifluoromethyl, 2,2-bis-fluoro ethyls and 2,2,2-trifluoroethyl.Be preferably trifluoromethyl.
Term halogen means fluorine, chlorine, bromine or iodine.
If " R 2" expression " halogen ", then this term preferably means fluorine, chlorine and bromine, and most preferably means fluorine.
If " R 3" expression " halogen ", then this term preferably means fluorine and chlorine, and most preferably means fluorine.
If " R 4" expression " halogen ", then this term preferably means fluorine, chlorine and bromine, and most preferably means fluorine.
If " R 5" expression " halogen ", then this term preferably means fluorine, chlorine and bromine, and most preferably means fluorine and chlorine.
If " R 6" expression " halogen ", then this term preferably means fluorine, chlorine and bromine, and most preferably means fluorine.
If " halogen " is aryl, heteroaryl, heterocyclic radical, aryloxy, heteroaryl oxygen base, aryl-(C 1-C 2) alkoxyl group, heteroaryl-(C 1-C 2) substituting group of alkoxyl group, Heteroarylthio, aryl sulfonyl or heteroarylsulfonyl, then this term means fluorine, chlorine, bromine or iodine.Preferred embodiment is fluorine and chlorine; Most preferably be chlorine.
Separately or mean phenyl or naphthyl with any term " aryl " combinationally used.Be preferably phenyl." aryl be optionally substituted " means the aryl being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " aryl be optionally substituted ", then this term mean be unsubstituted independently, through monosubstituted, replace through two or replace through three and (to be preferably unsubstituted or through monosubstituted, and most preferably through monosubstituted) group mentioned above (be preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.These substituting groups are preferably independently selected from by halogen and (C 1-C 4) alkoxyl group composition group.The example of these aryl be optionally substituted is phenyl, the chloro-phenyl of 2-, the chloro-phenyl of 3-, 2-methoxyl group-phenyl and 4-methoxyl group-phenyl.
If R 1represent " mono-substituted (the C of the aryl through being optionally substituted 1-C 4) alkyl "; then this term " aryl be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (to be preferably unsubstituted or through monosubstituted or through two replacements; and be most preferably unsubstituted or through monosubstituted) group mentioned above (being preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) alkyl sulphonyl, cyano group, phenyl and 5-methyl-tetrazole-1-base.Substituting group is preferably independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) alkyl sulphonyl, phenyl and 5-methyl-tetrazole-1-base.Substituting group is more preferably independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.In addition, this term " aryl be optionally substituted " can represent 2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine base.The example of these aryl be optionally substituted is phenyl, the fluoro-phenyl of 2-, the fluoro-phenyl of 3-, the fluoro-phenyl of 4-, the chloro-phenyl of 2-, the chloro-phenyl of 3-, the chloro-phenyl of 4-, 2, 3-Dichloro-phenyl, 2, 6-Dichloro-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyl group-phenyl, 3-methoxyl group-phenyl, 4-methoxyl group-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-Metlianesulfonyl-phenyl, biphenyl-4-base, 4-(5-methyl-tetrazole-1-base)-phenyl and 2, 3-dihydro-benzo [1, 4] dioxine-6-base (and is especially phenyl, the fluoro-phenyl of 2-, the fluoro-phenyl of 3-, the fluoro-phenyl of 4-, the chloro-phenyl of 2-, the chloro-phenyl of 3-, the chloro-phenyl of 4-, 2, 3-Dichloro-phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyl group-phenyl, 3-methoxyl group-phenyl, 2-trifluoromethyl-phenyl and 3-trifluoromethyl-phenyl).Other examples of these aryl be optionally substituted are naphthyl, 2, 3-difluorophenyl, 2, 4-difluorophenyl, 2, 5-difluorophenyl, 2, 6-difluorophenyl, 2, 4-Dichloro-phenyl, 2, 5-Dichloro-phenyl, the bromo-phenyl of 2-, the fluoro-phenyl of the chloro-6-of 2-, the fluoro-phenyl of the chloro-5-of 2-, the fluoro-phenyl of the chloro-2-of 5-, 2, 3-Dimethvl-phenyl, 2, 4-Dimethvl-phenyl, 2, 6-Dimethvl-phenyl, 2, 4, 6-trimethyl-phenyl, 2, 3-dimethoxy-phenylf, 2, 4-dimethoxy-phenylf, 2, 6-dimethoxy-phenylf, 4-trifluoromethyl-phenyl, 2-cvano-phenyl (and be especially 2, 3-difluorophenyl, 2, 4-difluorophenyl, 2, 4-Dichloro-phenyl, the fluoro-phenyl of the chloro-6-of 2-, 2, 3-Dimethvl-phenyl and 2, 4-Dimethvl-phenyl).In a preferred embodiment, if X represents-NH-, then this term " aryl be optionally substituted " preferably means and to be unsubstituted or through mono-substituted phenyl, wherein this substituting group is selected from halogen or (C 1-C 4) alkoxyl group (being especially selected from fluorine, chlorine or methoxyl group).In another preferred embodiment, if X represents-O-, then this term " aryl be optionally substituted " preferably mean be unsubstituted, through monosubstituted, replace through two or replace through three (be preferably unsubstituted, through monosubstituted or through two replacements) phenyl, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl and cyano group (and being preferably selected from fluorine, chlorine, methyl, methoxyl group and trifluoromethyl).In another preferred embodiment, if X represents a key, then this term " aryl be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three and (be preferably unsubstituted, through monosubstituted or through two replacements, and be most preferably unsubstituted or through monosubstituted) phenyl or naphthyl (preferred phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) alkyl sulphonyl, phenyl and 5-methyl-tetrazole-1-base (and being preferably selected from fluorine, chlorine, methyl, methoxyl group and trifluoromethyl).
If R 1represent " mono-substituted (the C of the aryl through being optionally substituted 2-C 4) thiazolinyl "; then this term " aryl be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (to be preferably unsubstituted or through monosubstituted; and most preferably through monosubstituted) group mentioned above (being preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.These substituting groups are preferably independently selected from by halogen and (C 1-C 4) alkyl composition group.The example of these aryl be optionally substituted is the fluoro-phenyl of 2-and 2-methylphenyl.
If R 1represent " mono-substituted (the C of the aryl through being optionally substituted 2-C 4) alkynyl "; then this term " aryl be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (to be preferably unsubstituted or through being singly substituted; and be most preferably unsubstituted) group mentioned above (being preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.The example of this aryl be optionally substituted is phenyl.
If R 1represent " mono-substituted (the C of the aryl through being optionally substituted 3-C 6) cycloalkyl "; then this term " aryl be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (be preferably unsubstituted, through monosubstituted or through two replacements; and be most preferably unsubstituted or through monosubstituted) group mentioned above (being preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.The example of these aryl be optionally substituted is phenyl, the fluoro-phenyl of 2-, the chloro-phenyl of 2-, the chloro-phenyl of 3-, the chloro-phenyl of 4-, 2,4-Dichloro-phenyl, 2-methylphenyl, 2-methoxyl group-phenyl and 2-trifluoromethyl-phenyl.Other examples of these aryl be optionally substituted are the fluoro-phenyl of 3-, the fluoro-phenyl of 4-, 3-methylphenyl, 4-methylphenyl, 3-methoxyl group-phenyl, 4-methoxyl group-phenyl, 3-trifluoromethyl-phenyl and 4-trifluoromethyl-phenyl.
If R 4represent " aryl be optionally substituted ", then this term mean be unsubstituted independently, through monosubstituted, replace through two or replace through three and (to be preferably unsubstituted or through monosubstituted, and most preferably through monosubstituted) group mentioned above (be preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.Substituting group is preferably independently selected from the group be made up of halogen.The example of this aryl be optionally substituted is the fluoro-phenyl of 4-.
If R 5represent " aryl be optionally substituted ", then this term mean be unsubstituted independently, through monosubstituted, replace through two or replace through three and (to be preferably unsubstituted or through monosubstituted, and most preferably through monosubstituted) group mentioned above (be preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.Substituting group is preferably independently selected from the group be made up of halogen.The example of this aryl be optionally substituted is the fluoro-phenyl of 4-.
If R 9represent " aryl be optionally substituted ", then this term mean be unsubstituted independently, through monosubstituted, replace through two or replace through three and (to be preferably unsubstituted or through being singly substituted, and be most preferably unsubstituted) group mentioned above (be preferably phenyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.The example of this aryl be optionally substituted is phenyl.
The term " aryloxy " be used alone or in combination refers to aryl-O-group, and wherein this aryl is as previously defined." aryloxy be optionally substituted " means the aryloxy being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " mono-substituted (the C of the aryloxy through being optionally substituted 1-C 4) alkyl "; then this term " aryloxy be optionally substituted " mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (to be preferably unsubstituted or through monosubstituted; and most preferably through monosubstituted) group mentioned above (being preferably phenoxy group), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl and phenyl.Substituting group is preferably independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl, and be most preferably selected from halogen and (C 1-C 4) alkyl.The example of these aryloxies be optionally substituted is phenoxy group, the fluoro-phenoxy group of 2-, the fluoro-phenoxy group of 3-, the fluoro-phenoxy group of 4-, the chloro-phenoxy group of 2-, the chloro-phenoxy group of 3-, the chloro-phenoxy group of 4-, 2-methyl-phenoxv, 3-methyl-phenoxv, 4-methyl-phenoxv and biphenyl-2-base.Other examples of these aryloxies be optionally substituted are 2,4-Dimehtyl-phenoxy, 2-Difluoro-phenoxy and 4-Difluoro-phenoxy.
Term " the aryl be optionally the substituted-(C be used alone or in combination 1-C 2) alkoxyl group " refer to aryl-(C as hereinbefore defined 1-C 2) alkoxyl group, wherein this aryl is unsubstituted as clearly defined or is substituted.
If R 1represent " the aryl through being optionally substituted-(C 1-C 2) mono-substituted (C of alkoxyl group 1-C 4) alkyl ", then this term " aryl be optionally substituted-(C 1-C 2) alkoxyl group " mean group mentioned above, wherein this term " aryl " means phenyl or naphthyl (being preferably phenyl).Aryl is unsubstituted independently, through monosubstituted, to replace through two or to replace (be preferably unsubstituted or through being singly substituted) through three, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.These substituting groups are preferably independently selected from by the following group formed: halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group.The example of these aryl is phenyl, the chloro-phenyl of 2-, the chloro-phenyl of 3-, the chloro-phenyl of 4-, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyl group-phenyl, 3-methoxyl group-phenyl and 4-methoxyl group-phenyl.
The term " aryl sulfonyl " be used alone or in combination refers to aryl-S (O) 2-group, wherein this aryl is as previously defined, and it is the rest part being connected to molecule via sulphur atom." aryl sulfonyl be optionally substituted " means the aryl sulfonyl being as previously defined unsubstituted as clearly defined or being substituted.
If R 9represent " aryl sulfonyl be optionally substituted "; then this term mean be unsubstituted independently, through monosubstituted, replace through two or replace through three (be preferably unsubstituted, through be singly substituted or through two replacements) group mentioned above (be preferably benzenesulfonyl), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl.These substituting groups are preferably independently selected from the group be made up of halogen (especially fluorine).The example of these aryl sulfonyls be optionally substituted is benzenesulfonyl, the fluoro-benzenesulfonyl of 2-, the fluoro-benzenesulfonyl of 3-and 3,4-Difluoro-benzenesulfonyl.
The term " heteroaryl " be used alone or in combination means 5 to 10 yuan of monocycles containing 1,2,3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1,2 or 3 heteroatoms, more preferably 1 or 2 heteroatoms) or Bicyclic aryl rings.The example of these heteroaryls is furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indyl, pseudoindoyl, benzofuryl, isobenzofuran-base, benzothienyl, indazolyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, benzotriazole base, benzo [2, 1, 3] oxadiazolyls, benzo [2, 1, 3] thiadiazolyl group, benzo [1, 2, 3] thiadiazolyl group, quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoxalinyl and phthalazinyl.Other examples are tetrazyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[2,3-c] pyridyl, pyrrolo-[3,2-b] pyridyl, pyrrolo-[3,2-c] pyridyl, 5H-pyrrolo-[2,3-b] pyrazinyl and imidazo [4,5-b] pyridyl.Preferred embodiment Wei isoxazolyl (the especially Wei isoxazole-3-base of these heteroaryls, isoxazole-4-base is Ji isoxazole-5-base), oxadiazolyl (be especially [1,2,4] oxadiazole-3-bases and [1,3,4] oxadiazole-2-bases), thiazolyl (is especially thiazol-2-yl, thiazole-4-yl and thiazole-5-base), imidazolyl (being especially imidazoles-2-base and imidazol-4 yl), pyrazolyl (being especially pyrazol-1-yl and pyrazole-3-yl), triazolyl (is especially [1,2,3] triazol-1-yl, [1,2,3] triazole-2-base and [1,2,3] triazole-4-yl), tetrazyl (being especially tetrazolium-5-base), pyridyl (is especially pyridine-2-base, pyridin-3-yl and pyridin-4-yl), pyrimidyl (being especially pyrimidine-4-yl and pyrimidine-5-base), pyrazinyl (being especially pyrazine-2-base), indyl (is especially indoles-1-base, indoles-2-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), benzothienyl (being especially thionaphthene-3-base), indazolyl (is especially indazole-1-base, indazole-2-base and indazole-3-base), benzimidazolyl-(being especially benzoglyoxaline-1-base and benzimidazolyl-2 radicals-Ji), benzoxazolyl (being especially benzoxazole-2-base), benzoisoxazole base (being especially benzoisoxazole-3-base), benzothiazolyl (being especially benzothiazole-2-base), pyrrolo-[2,3-b] pyridyl (being especially pyrrolo-[2,3-b] pyridine-1-base), pyrrolo-[2,3-c] pyridyl (being especially pyrrolo-[2,3-c] pyridine-1-base), pyrrolo-[3,2-b] pyridyl (being especially pyrrolo-[3,2-b] pyridine-1-base), pyrrolo-[3,2-c] pyridyl (being especially pyrrolo-[3,2-c] pyridine-1-base), 5H-pyrrolo-[2,3-b] pyrazinyl (being especially 5H-pyrrolo-[2,3-b] pyrazine-5-base), imidazo [4,5-b] pyridyl (being especially imidazo [4,5-b] pyridine-6-base) and quinolyl (are especially quinoline-6-base, quinoline-7-base and quinoline-8-yl).More preferably the example Wei isoxazolyl (especially Wei isoxazole-4-base) of these heteroaryls, oxadiazolyl (be especially [1,2,4] oxadiazole-3-bases), thiazolyl (being especially thiazole-4-yl), imidazolyl (being especially imidazoles-2-base and imidazol-4 yl), pyrazolyl (being especially pyrazole-3-yl), triazolyl (is especially [1,2,3] triazol-1-yl, [1,2,3] triazole-2-base and [1,2,3] triazole-4-yl), pyridyl (being especially pyridin-3-yl), pyrimidyl (being especially pyrimidine-5-base), indyl (is especially indoles-1-base, indoles-2-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), benzothienyl (being especially thionaphthene-3-base), indazolyl (being especially indazole-2-base), benzimidazolyl-(being especially benzoglyoxaline-1-base and benzimidazolyl-2 radicals-Ji), benzoisoxazole base (being especially benzoisoxazole-3-base), benzothiazolyl (being especially benzothiazole-2-base) and quinolyl (being especially quinoline-6-base and quinoline-7-base)." heteroaryl be optionally substituted " means the heteroaryl being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " mono-substituted (the C of the heteroaryl through being optionally substituted 1-C 4) alkyl ", then this term " heteroaryl " means group mentioned above.Preferred embodiment Wei isoxazolyl (the especially Wei isoxazole-3-base of these heteroaryls, isoxazole-4-base is Ji isoxazole-5-base), thiazolyl (is especially thiazol-2-yl, thiazole-4-yl and thiazole-5-base), imidazolyl (being especially imidazoles-2-base and imidazol-4 yl), pyrazolyl (being especially pyrazol-1-yl and pyrazole-3-yl), triazolyl (being especially [1,2,3] triazole-4-yl), pyridyl (being especially pyridine-2-base and pyridin-3-yl), pyrimidyl (being especially pyrimidine-4-yl and pyrimidine-5-base), pyrazinyl (being especially pyrazine-2-base), indyl (is especially indoles-1-base, indoles-2-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), benzothienyl (being especially thionaphthene-3-base), indazolyl (is especially indazole-1-base, indazole-2-base and indazole-3-base), benzimidazolyl-(being especially benzoglyoxaline-1-base and benzimidazolyl-2 radicals-Ji), benzoxazolyl (being especially benzoxazole-2-base), benzoisoxazole base (being especially benzoisoxazole-3-base), benzothiazolyl (being especially benzothiazole-2-base), pyrrolo-[2,3-b] pyridyl (being especially pyrrolo-[2,3-b] pyridine-1-base), pyrrolo-[2,3-c] pyridyl (being especially pyrrolo-[2,3-c] pyridine-1-base), pyrrolo-[3,2-b] pyridyl (being especially pyrrolo-[3,2-b] pyridine-1-base), pyrrolo-[3,2-c] pyridyl (being especially pyrrolo-[3,2-c] pyridine-1-base), 5H-pyrrolo-[2,3-b] pyrazinyl (being especially 5H-pyrrolo-[2,3-b] pyrazine-5-base) and quinolyl (being especially quinoline-6-base and quinoline-7-base).More preferably the example of these heteroaryls is thiazolyl (being especially thiazole-4-yl), imidazolyl (being especially imidazoles-2-base and imidazol-4 yl), triazolyl (is especially [1, 2, 3] triazole-4-yl), indyl (is especially indoles-1-base, indoles-2-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), benzothienyl (being especially thionaphthene-3-base), indazolyl (being especially indazole-2-base), benzimidazolyl-(being especially benzoglyoxaline-1-base and benzimidazolyl-2 radicals-Ji), benzoisoxazole base (being especially benzoisoxazole-3-base), benzothiazolyl (being especially benzothiazole-2-base) and quinolyl (being especially quinoline-6-base and quinoline-7-base).Most preferably be imidazolyl (being especially imidazol-4 yl), indyl (being especially indol-3-yl), benzofuryl (being especially cumarone-3-base), benzoisoxazole base (being especially benzoisoxazole-3-base) and quinolyl (being especially quinoline-6-base).If X represents-O-, then preferred embodiment Wei isoxazolyl (especially Wei isoxazole-3-base, isoxazole-4-base is Ji isoxazole-5-base), thiazolyl (is especially thiazol-2-yl, thiazole-4-yl and thiazole-5-base), imidazolyl (being especially imidazol-4 yl), pyrazolyl (being especially pyrazol-1-yl and pyrazole-3-yl), pyridyl (being especially pyridin-3-yl), pyrimidyl (being especially pyrimidine-4-yl and pyrimidine-5-base), pyrazinyl (being especially pyrazine-2-base), indazolyl (being especially indazole-1-base and indazole-3-base), benzimidazolyl-(being especially benzoglyoxaline-1-base), benzoxazolyl (being especially benzoxazole-2-base) and benzoisoxazole base (being especially benzoisoxazole-3-base).If X represents a key, then preferred embodiment is thiazolyl (being especially thiazole-4-yl), imidazolyl (being especially imidazoles-2-base and imidazol-4 yl), triazolyl (being especially [1,2,3] triazole-4-yl), pyridyl (being especially pyridine-2-base and pyridin-3-yl), indyl (is especially indoles-1-base, indoles-2-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), benzothienyl (being especially thionaphthene-3-base), indazolyl (being especially indazole-1-base and indazole-2-base), benzimidazolyl-(being especially benzoglyoxaline-1-base and benzimidazolyl-2 radicals-Ji), benzoisoxazole base (being especially benzoisoxazole-3-base), benzothiazolyl (being especially benzothiazole-2-base), pyrrolo-[2,3-b] pyridyl (being especially pyrrolo-[2,3-b] pyridine-1-base), pyrrolo-[2,3-c] pyridyl (being especially pyrrolo-[2,3-c] pyridine-1-base), pyrrolo-[3,2-b] pyridyl (being especially pyrrolo-[3,2-b] pyridine-1-base), pyrrolo-[3,2-c] pyridyl (being especially pyrrolo-[3,2-c] pyridine-1-base), 5H-pyrrolo-[2,3-b] pyrazinyl (being especially 5H-pyrrolo-[2,3-b] pyrazine-5-base) and quinolyl (being especially quinoline-6-base and quinoline-7-base), if X represents a key, then most preferably be imidazolyl (being especially imidazol-4 yl), indyl (being especially indoles-1-base and indol-3-yl), benzofuryl (being especially cumarone-3-base), indazolyl (being especially indazole-1-base), benzoisoxazole base (being especially benzoisoxazole-3-base) and pyrrolo-[2,3-b] pyridyl (being especially pyrrolo-[2,3-b] pyridine-1-base).Heteroaryl is unsubstituted independently, through monosubstituted, replace through two or replace through three and (be preferably unsubstituted, through monosubstituted or through two replacements, and be most preferably unsubstituted or through monosubstituted), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, trifluoromethyl, cyano group and phenyl, wherein this phenyl is unsubstituted or monosubstituted or two replacements through methyl.Substituting group is preferably independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and phenyl, wherein this phenyl is unsubstituted or monosubstituted or two replacements through methyl.Substituting group is most preferably independently selected from by (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group composition group.The example of these heteroaryls be optionally substituted is 2-methYl-thiazol-4-base, 1-phenyl imidazole-2-base, 3-(2, 3-Dimethvl-phenyl)-imidazol-4 yl (preferably), 3-phenyl-[1, 2, 3] triazole-4-yl, indoles-1-base, 5-Methoxv-indole-2-base, indol-3-yl, the fluoro-indol-3-yl of 5-, the chloro-indol-3-yl of 5-, 1-Methvl-indole-3-base (preferably), 2-Methvl-indole-3-base (preferably), 1-Ethyl-2-Methyl-indol-3-yl, 5-Methoxv-indole-3-base (preferably), 6-Mehtoxy-Benzofuran-3-base, thionaphthene-3-base, the chloro-thionaphthene of 5--3-base, indazole-2-base, benzoglyoxaline-1-base, benzimidazolyl-2 radicals-Ji, benzoisoxazole-3-base, 5-methyl-benzoisoxazole-3-base, 5-methoxyl group-benzoisoxazole-3-base (preferably), benzothiazole-2-base, quinoline-6-base and quinoline-7-base.Other examples are 4-methyl-isoxazole-3-base, 5-methyl-isoxazole-3-base, 3,5-dimethyl-isoxazole-4-base, 3-methyl-isoxazole-5-base, thiazol-2-yl, 4-methYl-thiazol-2-base, 5-methYl-thiazol-2-base, 2-methyl-thiazole-5-Ji, 4-methyl-thiazole-5-Ji, 4-methyl pyrazole-1-base, 3,5-Dimethyl-pyrazol-1-base, 2-methyl pyrazole-3-base, 2,5-Dimethyl-pyrazol-3-base, 2-ethyl-5-methyl pyrazole-3-base, 1,5-Dimethyl-pyrazol-3-base, 3-methyl-imidazoles-4-base, 2,6-dimethyl-pyridin-3-yl, pyrimidine-4-yl, pyrimidine-5-base, pyrazine-2-base, 3-Methvl-indole-1-base, 6-Methvl-indole-1-base, 6-Methoxv-indole-1-base, 4,6-dimethoxy-indoles-1-base, the chloro-indoles of 6--1-base, 2-trifluoromethyl-indoles-1-base, indazole-1-base, the fluoro-indazole of 4--1-base, the fluoro-indazole of 5--1-base, the fluoro-indazole of 6--1-base, the fluoro-indazole of 7--1-base, the fluoro-3-methyl-indazol of 4--1-base, the fluoro-3-methyl-indazol of 6--1-base, the fluoro-3-methyl-indazol of 7--1-base, the chloro-indazole of 4--1-base, the chloro-indazole of 5--1-base, the chloro-indazole of 6--1-base, the chloro-indazole of 7--1-base, the chloro-3-methyl-indazol of 4--1-base, the chloro-3-methyl-indazol of 6--1-base, 3-methyl-indazol-1-base, 1-methyl-indazol-3-base, the chloro-indazole of 3--1-base, benzoxazole-2-base, 3-chloro-5H-pyrrolo-[2,3-b] pyrazine-5-base and 6-methoxyl group-pyrrolo-[2,3-b] pyridine-1-base.
If R 1represent " mono-substituted (the C of the heteroaryl through being optionally substituted 3-C 6) cycloalkyl ", then this term " heteroaryl " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryls containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms).The example of these 5 yuan or 6 yuan bicyclic heteroaryls is furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.The preferred embodiment of this heteroaryl is thiazolyl (being especially thiazole-5-base).Heteroaryl is unsubstituted independently, through monosubstituted, replace through two or replace through three and (be preferably unsubstituted, through monosubstituted or through two replacements, and most preferably replace through two), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and trifluoromethyl.Substituting group is most preferably be selected from (C 1-C 4) alkyl.The example of this heteroaryl be optionally substituted is 2,4-dimethyl thiazol-5-base.
If R 4represent " heteroaryl be optionally substituted ", then this term " heteroaryl " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryls containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms).The example of these 5 yuan or 6 yuan bicyclic heteroaryls is furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.The preferred embodiment of this heteroaryl is pyrimidyl (being especially pyrimidine-5-base).Heteroaryl is unsubstituted independently, through monosubstituted, replace through two or replace through three and (be preferably unsubstituted, through to be singly substituted or through two replacements, and be most preferably unsubstituted), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group.Substituting group is most preferably be selected from (C 1-C 4) alkyl.The example of this heteroaryl be optionally substituted is pyrimidine-5-base.
If R 5represent " heteroaryl be optionally substituted ", then this term " heteroaryl " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryls containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms).The example of these 5 yuan or 6 yuan bicyclic heteroaryls is furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.The preferred embodiment Wei oxadiazolyl of these heteroaryls (be especially [1,2,4] oxadiazole-3-bases), triazolyl (are especially [1,2,3] triazol-1-yl and [1,2,3] triazole-2-base) and pyrimidyl (being especially pyrimidine-5-base).Heteroaryl is unsubstituted independently, through monosubstituted, to replace through two or replace through three (to be preferably unsubstituted or through being singly substituted, and to be most preferably unsubstituted), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and sulfydryl (preferably).The example of these heteroaryls be optionally substituted is 5-sulfydryl-[1,2,4] oxadiazole-3-base (5-sulfo-s-4,5-dihydro-[tautomers of 1,2,4] oxadiazole-3-bases), [1,2,3] triazol-1-yl (preferably), [1,2,3] triazole-2-base (preferably) and pyrimidine-5-base.
If R 10represent " heteroaryl be optionally substituted ", then this term " heteroaryl " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryls containing 1,2,3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 2,3 or 4 heteroatomss).The example of these 5 yuan or 6 yuan bicyclic heteroaryls is furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.(especially Wei isoxazole-5-base), oxadiazolyl (is especially [1 to the preferred embodiment Wei isoxazolyl of these heteroaryls, 2,4] oxadiazole-3-bases and [1,3,4] oxadiazole-2-bases) and tetrazyl (being especially tetrazolium-5-base).Heteroaryl is unsubstituted independently, through monosubstituted, to replace through two or to replace (be preferably unsubstituted or through being singly substituted) through three, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and hydroxyl (preferably).The example of these heteroaryls be optionally substituted is the tautomer of 3-hydroxyl-isoxazole-5-base (isoxazole-3 (2H)-one-5-base), 5-hydroxyl-[1,2,4] oxadiazole-3-bases (1,2, the tautomer of 4-oxadiazole-5 (4H)-one-3-base), 5-hydroxyl-[1,3,4] oxadiazole-2-bases (1, the tautomer of 3,4-oxadiazole-5 (4H)-one-2-base) and tetrazolium-5-base.
The term " heteroaryl oxygen base " be used alone or in combination refers to heteroaryl-O-group, and wherein this heteroaryl is as previously defined." the heteroaryl oxygen base be optionally substituted " means the heteroaryl oxygen base being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " mono-substituted (the C of heteroaryl oxygen base through being optionally substituted 1-C 4) alkyl ", then this term " the heteroaryl oxygen base be optionally substituted " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryl oxygen bases containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms) in heteroaryl moieties.The example of these 5 yuan or 6 yuan bicyclic heteroaryl oxygen bases is furyl oxygen Ji, oxazolyl oxygen base, isoxazolyl oxygen Ji, oxadiazolyl oxygen base, thienyl oxygen base, thiazolyl oxygen base, isothiazolyl oxygen base, thiazoldiazolioxo, pyrryl oxygen base, imidazolyl oxygen base, pyrazoloxy, triazolyl oxygen base, pyridyl oxygen base, pyrimidyl oxygen base, pyridazinyl oxygen base and pyrazinyl oxygen base.The preferred embodiment of this heteroaryl oxygen base is pyridyl oxygen base (being especially pyridin-3-yl oxygen base).Other preferred embodiments are imidazo [4,5-b] pyridyl oxygen base (being especially imidazo [4,5-b] pyridine-6-base oxygen base) and quinolyl oxygen base (being especially quinoline-8-yl oxygen base).Heteroaryl oxygen base is unsubstituted independently, through monosubstituted, replace through two or replace through three and (be preferably unsubstituted, through to be singly substituted or through two replacements, and most preferably replace through two), wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, 2-Hydroxy-ethoxy, cyano group ,-C (O) NH 2and trifluoromethyl (is preferably selected from halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group, and be most preferably selected from (C 1-C 4) alkyl).The example of the heteroaryl oxygen base that this is optionally substituted is 2,6-dimethyl-pyridin-3-yl oxygen base.Other examples are pyridin-3-yl oxygen base, 2-fluoro-pyridin-3-yl oxygen base, 5-fluoro-pyridin-3-yl oxygen base, 2-chloro-pyridin-3-yl oxygen base, 4-chloro-pyridin-3-yl oxygen base, 5-chloro-pyridin-3-yl oxygen base, 6-chloro-pyridin-3-yl oxygen base, 2-methvl-pyridinium-3-base oxygen base, 5-methvl-pyridinium-3-base oxygen base, 6-methvl-pyridinium-3-base oxygen base, 5-methyl-2-methoxv-pyridine-3-base oxygen base, 5-methoxv-pyridine-3-base oxygen base, 6-methoxv-pyridine-3-base oxygen base, 2, 6-dimethoxy-pyridin-3-base oxygen base, 5, 6-dimethoxy-pyridin-3-base oxygen base, 2-(2-Hydroxy-ethoxy)-pyridin-3-yl oxygen base, 2-Cyano-pyridin-3-base oxygen base, 2-carbamyl-pyridin-3-yl oxygen base, 6-trifluoromethylpyridin-3-base oxygen base, 2, 6-Dichloro-pendin-4-base oxygen base, 3-methyl-imidazoles also [4, 5-b] pyridine-6-base oxygen base and quinoline-8-yl oxygen base.
The term " Heteroarylthio " be used alone or in combination refers to heteroaryl-S-group, and wherein this heteroaryl is as previously defined." Heteroarylthio be optionally substituted " means the Heteroarylthio being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " mono-substituted (the C of the Heteroarylthio through being optionally substituted 1-C 4) alkyl ", then this term " Heteroarylthio be optionally substituted " means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryl sulfenyls containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms) in heteroaryl moieties.The example of these 5 yuan or 6 yuan bicyclic heteroaryl sulfenyls is furyl sulfenyl, oxazolyl sulfenyl, isoxazolyl sulfenyl, oxadiazolyl sulfenyl, thienyl sulfenyl, thiazolyl sulfenyl, isothiazolyl sulfenyl, thiadiazolyl group sulfenyl, pyrryl sulfenyl, imidazolyl sulfenyl, pyrazolyl sulfenyl, triazolyl sulfenyl, pyridinylthio, pyrimidine-based sulfur-base, pyridazinyl sulfenyl and pyrazinyl sulfenyl.The preferred embodiment of this Heteroarylthio is triazolyl sulfenyl (being especially [1,2,3] triazole-4-yl sulfenyl).Heteroarylthio is unsubstituted independently, through monosubstituted, to replace through two or to replace (preferably through being singly substituted) through three, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and phenyl (and being preferably selected from phenyl).The example of this Heteroarylthio be optionally substituted is 3-phenyl-3H-[1,2,3] triazole-4-yl sulfenyl.
The term " heteroarylsulfonyl " be used alone or in combination refers to heteroaryl-S (O) 2-group, wherein this heteroaryl is as previously defined, and it is the rest part being connected to molecule via sulphur atom." heteroarylsulfonyl be optionally substituted " means the heteroarylsulfonyl being as previously defined unsubstituted as clearly defined or being substituted.
If R 9represent " heteroarylsulfonyl be optionally substituted ", then this term means group mentioned above.Be preferably 5 yuan or 6 yuan of bicyclic heteroaryl alkylsulfonyls containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms) in heteroaryl moieties.The example of these 5 yuan or 6 yuan bicyclic heteroaryl alkylsulfonyls is furanylsulfonyl, oxazolyl alkylsulfonyl, isoxazolyl alkylsulfonyl, oxadiazolyl alkylsulfonyl, thienyl sulphonyl base, thiazolyl alkylsulfonyl, isothiazolyl alkylsulfonyl, thiadiazolyl group alkylsulfonyl, pyrryl alkylsulfonyl, imidazolyl alkylsulfonyl, pyrazolyl alkylsulfonyl, triazolyl alkylsulfonyl, pyridyl sulfonyl, pyrimidyl alkylsulfonyl, pyridazinyl alkylsulfonyl and pyrazinyl alkylsulfonyl.The preferred embodiment Wei isoxazolyl alkylsulfonyl (especially Wei isoxazole-4-alkylsulfonyl) of this heteroarylsulfonyl.Heteroarylsulfonyl is unsubstituted independently, through monosubstituted, to replace through two or to replace (preferably through two replace) through three, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group (and be preferably selected from (C 1-C 4) alkyl).The example of this heteroarylsulfonyl be optionally substituted is 3,5-dimethyl-isoxazole-4-alkylsulfonyl.
Term " the heteroaryl be optionally the substituted-(C be used alone or in combination 1-C 2) alkoxyl group " refer to heteroaryl-(C as hereinbefore defined 1-C 2) alkoxyl group, wherein this heteroaryl is unsubstituted as clearly defined or is substituted.
If R 1represent " the heteroaryl through being optionally substituted-(C 1-C 2) mono-substituted (C of alkoxyl group 1-C 4) alkyl ", then this term " heteroaryl be optionally substituted-(C 1-C 2) alkoxyl group " mean group mentioned above, wherein this term " heteroaryl " means heteroaryl as hereinbefore defined and 5 yuan or 6 yuan of bicyclic heteroaryls being preferably containing 1,2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (preferably 1 or 2 heteroatoms).As " the heteroaryl be optionally substituted-(C 1-C 2) alkoxyl group " and in the example of these 5 yuan or 6 yuan bicyclic heteroaryls used be furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.The preferred embodiment of this heteroaryl is pyrazolyl (being especially pyrazole-3-yl).As " the heteroaryl be optionally substituted-(C 1-C 2) alkoxyl group " and in heteroaryl used be unsubstituted independently, through monosubstituted, to replace through two or to replace (preferably through monosubstituted) through three, wherein these substituting groups are independently selected from by the following group formed: halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group (and be preferably selected from (C 1-C 4) alkyl).As " the heteroaryl be optionally substituted-(C 1-C 2) alkoxyl group " and in the example of this heteroaryl be optionally substituted used be 1-methyl isophthalic acid H-pyrazole-3-yl.The heteroaryl be optionally substituted-(C 1-C 2) preferred embodiment of alkoxyl group is 1-methyl isophthalic acid H-pyrazole-3-yl methoxyl group.
The term " heterocyclic radical " be used alone or in combination refers to the saturated monocyclic moeity of heteroatomic 5 to 7 the ring Cheng Yuan being selected from nitrogen, oxygen and sulphur containing 1 or 2, should be appreciated that heterocyclic radical not containing 2 sulphur atoms.The sulphur atom of heterocyclic radical can be oxidised form, that is in sulfoxide or alkylsulfonyl form.Heterocyclic radical can optionally and phenyl ring ring." heterocyclic radical be optionally substituted " means the heterocyclic radical being as previously defined unsubstituted as clearly defined or being substituted.
If R 1represent " mono-substituted (the C of the heterocyclic radical through being optionally substituted 1-C 4) alkyl ", then this term " heterocyclic radical " means group mentioned above.The example of these heterocyclic radicals is pyrrolidyl, imidazolidyl, oxazolidinyl, thiazolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, dioxane base, indoline base, isoindoline base, dihydro benzo furyl, tetrahydric quinoline group, tetrahydro isoquinolyl, tetrahydroquinoxaline base, look alkyl (chromanyl, chromanyl), Er hydrogen benzoxazinyl, dihydrobenzo thiazinyl and dihydrobenzo dioxine base.Preferred embodiment is thiazolidyl (being especially thiazolidine-3-base), indoline base (being especially indoline-1-base), isoindoline base (being especially isoindoline-2-base), tetrahydric quinoline group (are especially 1,2,3,4-tetrahydroquinoline-1-base) and Er hydrogen benzoxazinyl (be especially 2,3-dihydro-benzo [Isosorbide-5-Nitrae] oxazine-4-base).Other preferred embodiments are pyrrolidyl (being especially pyrrolidin-1-yl).Heterocyclic radical is unsubstituted independently, through monosubstituted, through two replace or through three replace (be preferably unsubstituted, through be singly substituted or through two replacements), wherein these substituting groups are independently selected from the group be made up of halogen, oxo base (oxo) and phenyl.The example of these heterocyclic radicals be optionally substituted is 4-oxo-2-Phenyl-thiazol alkane-3-base, indoline-1-base, isoindoline-2-base, 1,2,3,4-tetrahydroquinoline-1-base and the chloro-3-oxo of 6--2,3-dihydros-benzo [Isosorbide-5-Nitrae] oxazine-4-base.Other examples are 2-oxo-pyrroli-1-base, 4-methyl-2-oxo-thiazolidin-3-base, 2-oxo-thiazolidin-3-base and 1-oxo-isoindoline-2-base.
Term " 10 yuan of unsaturated loop systems of part " means tetralyl (being especially 1,2,3,4-naphthane-2-base) or chromenyl (being especially 2H-chromene-3-base).
2) another embodiment of the present invention relates to embodiment 1) formula (I) compound, be also formula (IP) compound,
Wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O or S;
R 1represent
(C 4-C 6) alkyl;
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted;
(C 2-C 4) thiazolinyl, its aryl through being optionally substituted is monosubstituted;
(C 2-C 4) alkynyl, its aryl through being optionally substituted is monosubstituted;
(C 3-C 6) cycloalkyl, its aryl through being optionally substituted is monosubstituted;
The aryl be optionally substituted; Or
10 yuan of unsaturated loop systems of part;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, (C 1-C 4) alkyl sulphonyl, benzenesulfonyl or (C 1-C 4) alkyl sulfonyl amino;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxyl group, halogen or (C 1-C 4) alkyl sulphonyl;
R 5represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group ,-CONH 2, the optionally aryl, the heteroaryl be optionally the substituted, (C that are substituted 1-C 4) alkyl sulphonyl, benzenesulfonyl or dimethylamino-alkylsulfonyl;
R 6represent hydrogen or halogen; Or
R 5and R 6form methylene-dioxy together;
R 7represent hydrogen or methyl;
R 8represent hydrogen or methyl; And
R 9represent the aryl sulfonyl be optionally substituted or the heteroarylsulfonyl be optionally substituted;
Its restricted condition is
(1) if X represents-NH-or a key, then R 1aryl not for being optionally substituted; And
(2) R 5and R 6in at least one be not hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
3) another embodiment of the present invention relates to embodiment 1) compound, wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O;
N represents 0 or 1;
R 1represent
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group or the Heteroarylthio that is optionally substituted monosubstituted;
(C 3-C 6) cycloalkyl, it is through (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) alkoxyl group is monosubstituted, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen or (C 1-C 4) alkyl sulphonyl;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 5represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group, the aryl be optionally substituted, the heteroaryl be optionally substituted or benzenesulfonyl;
R 6represent hydrogen or halogen; Or
R 7represent hydrogen; And
R 10represent-C (O) OH ,-C (O) NH-CN ,-C (O) NH-OH ,-C (O) NH-S (O) 2cF or the heteroaryl be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
4) another embodiment of the present invention relates to embodiment 1) or 2) compound, wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O;
R 1represent
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group or the Heteroarylthio that is optionally substituted monosubstituted; Or
(C 3-C 6) cycloalkyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen or (C 1-C 4) alkyl sulphonyl;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 5represent (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group, the aryl be optionally substituted, the heteroaryl be optionally substituted or benzenesulfonyl;
R 6represent hydrogen or halogen; And
R 7represent hydrogen or methyl;
And the salt of these compounds (especially pharmaceutically acceptable salt).
5) another embodiment of the present invention relates to embodiment 1) to 4) in any one compound, wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O;
R 1represent
(C 1-C 4) alkyl, its aryl, the heteroaryl be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, methyl, methoxyl group, trifluoromethyl or halogen;
R 3represent hydrogen or fluorine;
R 4represent hydrogen, methoxyl group or fluorine;
R 5represent trifluoromethyl, halogen, cyano group, the aryl be optionally substituted or the heteroaryl be optionally substituted;
R 6represent hydrogen or fluorine; And
R 7represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
6) another embodiment of the present invention relates to embodiment 1) to 5) in any one compound, wherein
X represents-O-or a key;
Y represents methylene radical;
Z represents O;
N represents 0 or 1;
R 1represent
(C 1-C 2) alkyl, its aryl, the heteroaryl be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group (aryl preferably through being optionally substituted or the heteroaryl be optionally substituted) is monosubstituted; Or
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, trifluoromethyl or fluorine (being preferably hydrogen or fluorine);
R 3represent hydrogen or fluorine;
R 4represent hydrogen;
R 5represent halogen or cyano group (being preferably chlorine);
R 6represent hydrogen;
R 7represent hydrogen; And
R 10represent-C (O) OH;
And the salt of these compounds (especially pharmaceutically acceptable salt).
7) another embodiment of the present invention relates to embodiment 1) or 2) compound, wherein
X represents-NH-;
Y represents (C 1-C 4) alkane two base (being preferably methylene radical);
Z represents O or S;
R 1represent (C 1-C 4) alkyl (be preferably methyl or ethyl), it is monosubstituted through phenyl, and this phenyl is unsubstituted or through halogen or (C 1-C 4) alkoxyl group (and preferably through chlorine or methoxyl group) is monosubstituted;
R 2represent hydrogen;
R 3represent hydrogen;
R 4represent hydrogen;
R 5represent halogen (preferred fluorine or chlorine);
R 6represent hydrogen;
R 7represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
8) another embodiment of the present invention relates to embodiment 1) or 2) compound, wherein
X represents-O-;
Y represents (C 1-C 4) alkane two base;
Z represents O;
R 1represent
(C 4-C 6) alkyl;
(C 1-C 4) alkyl, it is through (C 1-C 4) alkoxyl group or the aryl that is optionally substituted monosubstituted; Or
The aryl be optionally substituted;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, (C 1-C 4) alkyl sulphonyl, benzenesulfonyl or (C 1-C 4) alkyl sulfonyl amino;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxyl group, halogen or (C 1-C 4) alkyl sulphonyl;
R 5represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group ,-CONH 2, the optionally aryl, the heteroaryl be optionally the substituted, (C that are substituted 1-C 4) alkyl sulphonyl, benzenesulfonyl or dimethylamino-alkylsulfonyl;
R 6represent hydrogen or halogen; Or
R 5and R 6form methylene-dioxy together;
R 7represent hydrogen or methyl;
Its restricted condition is R 5and R 6in at least one be not hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
9) another embodiment of the present invention relates to embodiment 1), 2) or 8) in any one compound, wherein
X represents-O-;
Y represents (C 1-C 4) alkane two base;
Z represents O;
R 1represent (C 1-C 4) alkyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, methyl, methoxyl group, trifluoromethyl or halogen;
R 3represent hydrogen, methoxyl group or fluorine;
R 4represent hydrogen, methoxyl group or fluorine;
R 5represent trifluoromethyl, halogen, cyano group, the aryl be optionally substituted or the heteroaryl be optionally substituted;
R 6represent hydrogen or fluorine;
R 7represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
10) another embodiment of the present invention relates to embodiment 1) compound, wherein
X represents-O-;
Y represents (C 1-C 2) alkane two base (being preferably methylene radical);
Z represents O;
N represents 0 or 1;
R 1represent (C 1-C 2) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted or the heteroaryl (aryl preferably through being optionally substituted or the heteroaryl be optionally substituted) that is optionally substituted be monosubstituted;
R 2represent hydrogen, methyl, methoxyl group, trifluoromethyl or halogen (being preferably hydrogen, trifluoromethyl or fluorine);
R 3represent hydrogen or halogen (being preferably hydrogen or fluorine);
R 4represent hydrogen, (C 1-C 4) alkoxy or halogen (being preferably hydrogen or fluorine);
R 5the heteroaryl (being preferably fluorine, chlorine or cyano group) representing halogen, cyano group, the aryl be optionally substituted or be optionally substituted;
R 6represent hydrogen;
R 7represent hydrogen; And
R 10represent-C (O) OH ,-C (O) NH-S (O) 2cF or the heteroaryl (being preferably-C (O) OH) be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
11) another embodiment of the present invention relates to embodiment 1) or 2) compound, wherein
X represents a key;
Y represents (C 1-C 4) alkane two base;
Z represents O;
R 1represent
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted;
(C 2-C 4) thiazolinyl, its aryl through being optionally substituted is monosubstituted;
(C 2-C 4) alkynyl, its aryl through being optionally substituted is monosubstituted; Or
(C 3-C 6) cycloalkyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen or halogen;
R 3represent hydrogen;
R 4represent hydrogen;
R 5represent halogen or cyano group;
R 6represent hydrogen;
R 7represent hydrogen;
R 8represent hydrogen or methyl; And
R 9represent the aryl sulfonyl be optionally substituted or the heteroarylsulfonyl be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
12) another embodiment of the present invention relates to embodiment 1) compound, wherein
X represents a key;
Y represents methylene radical;
Z represents O;
N represents 0 or 1;
R 1represent
(C 1-C 4) alkyl (preferably (C 1-C 3) alkyl), it is through (C 3-C 6) cycloalkyl, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or the aryl-(C be optionally substituted 1-C 2) alkoxyl group (aryl preferably through being optionally substituted, the heteroaryl be optionally substituted, the aryloxy be optionally substituted or the aryl-(C be optionally substituted 1-C 2) alkoxyl group) monosubstituted;
Cyclopropyl, it replaces through methyl two, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted monosubstituted (aryl preferably through being optionally substituted is monosubstituted);
R 2represent hydrogen or halogen (being preferably hydrogen or fluorine);
R 3represent hydrogen or halogen (being preferably hydrogen or fluorine);
R 4represent hydrogen;
R 5represent halogen or cyano group (being preferably fluorine or chlorine);
R 6represent hydrogen;
R 7represent hydrogen; And
R 10represent-C (O) OH;
And the salt of these compounds (especially pharmaceutically acceptable salt).
13) another embodiment of the present invention relates to embodiment 1), 2), 11) or 12) in any one compound, wherein
X represents a key;
Y represents methylene radical;
Z represents O;
R 1represent
(C 1-C 4) alkyl, its aryl, the heteroaryl be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen or fluorine;
R 3represent hydrogen;
R 4represent hydrogen;
R 5represent fluorine, chlorine or cyano group;
R 6represent hydrogen;
R 7represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
14) another embodiment of the present invention relates to embodiment 1) compound, wherein
X represents-NH-,-O-or a key;
Y represents methylene radical;
Z represents O;
N represents 0;
R 1represent
(C 1-C 4) alkyl (preferably (C 1-C 2) alkyl), its aryl, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group is monosubstituted;
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen or halogen (being preferably hydrogen or fluorine);
R 3represent hydrogen or halogen (being preferably hydrogen or fluorine);
R 4represent hydrogen;
R 5represent halogen (preferred fluorine or chlorine);
R 6represent hydrogen;
R 7represent hydrogen;
R 10represent-C (O) OH;
And the salt of these compounds (especially pharmaceutically acceptable salt).
15) another embodiment of the present invention relates to embodiment 1) to 5), 7) or 14) in any one compound, wherein
X represents-NH-;
And the salt of these compounds (especially pharmaceutically acceptable salt).
16) another embodiment of the present invention relates to embodiment 1) to 6), 8) to 10) or 14) in any one compound, wherein
X represents-O-;
And the salt of these compounds (especially pharmaceutically acceptable salt).
17) another embodiment of the present invention relates to embodiment 1) to 6) or 11) to 14) in any one compound, wherein
X represents a key;
And the salt of these compounds (especially pharmaceutically acceptable salt).
18) another embodiment of the present invention relates to embodiment 1) to 5), 7) to 11) or 15) to 17) in any one compound, wherein
Y represents methylene radical, second-1,1-bis-base or third-1,3 two bases (and being preferably methylene radical or second-1,1-bis-base); And the salt of these compounds (especially pharmaceutically acceptable salt).
19) another embodiment of the present invention relates to embodiment 1) to 11) or 15) to 17) in any one compound, wherein
Y represents methylene radical or (R)-configuration second-1,1-bis-base (and being preferably methylene radical);
And the salt of these compounds (especially pharmaceutically acceptable salt).
20) another embodiment of the present invention relates to embodiment 1) to 19) in any one compound, wherein
Z represents O;
And the salt of these compounds (especially pharmaceutically acceptable salt).
21) another embodiment of the present invention relates to embodiment 1) or 3) to 20) and in any one compound, wherein
N represents 0;
And the salt of these compounds (especially pharmaceutically acceptable salt).
22) another embodiment of the present invention relates to embodiment 1) to 20) in any one compound, wherein n represents 1;
And the salt of these compounds (especially pharmaceutically acceptable salt).
23) another embodiment of the present invention relates to embodiment 1), 2), 8) or 15) to 22) in any one compound, wherein
R 1represent (C 4-C 6) alkyl;
And the salt of these compounds (especially pharmaceutically acceptable salt).
24) another embodiment of the present invention relates to embodiment 1) or 15) to 22) and in any one compound, wherein
R 1represent
(C 1-C 4) alkyl (preferably (C 1-C 2) alkyl), it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted; Or
(C 3-C 6) cycloalkyl (being preferably cyclopropyl), it is through (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) alkoxyl group is monosubstituted, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
25) another embodiment of the present invention relates to embodiment 1), 3) or 15) to 22) in any one compound, wherein
R 1represent
(C 1-C 4) alkyl (preferably (C 1-C 3) alkyl), it is through (C 3-C 6) cycloalkyl, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group or heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, it is through (C 1-C 4) alkyl is monosubstituted or two replace, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted (preferably through (C 1-C 4) alkyl monosubstituted or two replace or aryl through being optionally substituted monosubstituted, and aryl most preferably through being optionally substituted is monosubstituted);
And the salt of these compounds (especially pharmaceutically acceptable salt).
26) another embodiment of the present invention relates to embodiment 1) to 4), 11) or 15) to 22) in any one compound, wherein
R 1represent
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group or the Heteroarylthio that is optionally substituted monosubstituted; Or
(C 3-C 6) cycloalkyl, its aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
27) another embodiment of the present invention relates to embodiment 1) to 5) or 11) to 22) in any one compound, wherein
R 1represent
(C 1-C 4) alkyl, its aryl, the heteroaryl be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
28) another embodiment of the present invention relates to embodiment 1) to 5) or 11) to 22) in any one compound, wherein
R 1represent (C 1-C 4) alkyl, its aryl, the heteroaryl be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group (and aryl preferably through being optionally substituted or heteroaryl of being optionally substituted) is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
29) another embodiment of the present invention relates to embodiment 1) to 6) or 10) to 28) in any one compound, wherein
(C 1-C 4) alkyl, (C 1-C 3) alkyl or (C 1-C 2) alkyl (if represent R 1) substituting group be selected from the aryl be optionally substituted or the heteroaryl be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
30) another embodiment of the present invention relates to embodiment 1) to 22) or 24) to 29) in any one compound, wherein through mono-substituted (C 1-C 4) alkyl (if represent R 1) be selected from methyl; The ethyl that 2 positions are substituted; And 3 n-propyls of being substituted of position;
And the salt of these compounds (especially pharmaceutically acceptable salt).
31) another embodiment of the present invention relates to embodiment 1), 3) or 15) to 22) in any one compound, wherein
R 1represent (C 3-C 6) cycloalkyl (being preferably cyclopropyl), it is through (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) alkoxyl group is monosubstituted, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
32) another embodiment of the present invention relates to embodiment 1), 3), 12) or 15) to 22) in any one compound, wherein
R 1represent (C 3-C 6) cycloalkyl (preferred cyclopropyl), its monosubstituted or through being optionally substituted heteroaryl of aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
33) another embodiment of the present invention relates to embodiment 1) to 6) or 11) to 22) in any one compound, wherein
R 1represent (C 3-C 6) cycloalkyl (be preferably cyclopropyl), its aryl through being optionally substituted is monosubstituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
34) another embodiment of the present invention relates to embodiment 1) to 5), 8) to 10) or 15) to 33) in any one compound, wherein
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl or halogen (and being preferably hydrogen, methyl, methoxyl group, trifluoromethyl, fluorine, chlorine or bromine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
35) another embodiment of the present invention relates to embodiment 1) to 6), 8) to 10) or 15) to 33) in any one compound, wherein
R 2represent hydrogen, (C 1-C 4) fluoroalkyl or halogen (and being preferably hydrogen, trifluoromethyl or fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
36) another embodiment of the present invention relates to embodiment 1) to 6) or 8) to 33) in any one compound, wherein
R 2represent halogen (and being preferably fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
37) another embodiment of the present invention relates to embodiment 1) to 33) in any one compound, wherein
R 2represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
38) another embodiment of the present invention relates to embodiment 1) to 6), 8) to 10), 12) or 14) to 37) in any one compound, wherein
R 3represent hydrogen or halogen (and being preferably hydrogen or fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
39) another embodiment of the present invention relates to embodiment 1) to 37) in any one compound, wherein
R 3represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
40) another embodiment of the present invention relates to embodiment 1) to 5), 8) to 10) or 15) to 39) in any one compound, wherein
R 4represent hydrogen, (C 1-C 4) alkoxy or halogen (and being preferably hydrogen, methoxyl group or fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
41) another embodiment of the present invention relates to embodiment 1) to 5), 8) to 10) or 15) to 39) in any one compound, wherein
R 4represent hydrogen or halogen (and being preferably hydrogen or fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
42) another embodiment of the present invention relates to embodiment 1) to 39) in any one compound, wherein
R 4represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
43) another embodiment of the present invention relates to embodiment 1) to 4), 8) or 15) to 42) in any one compound, wherein
R 5represent (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group, the aryl be optionally substituted, the heteroaryl be optionally substituted or benzenesulfonyl;
And the salt of these compounds (especially pharmaceutically acceptable salt).
44) another embodiment of the present invention relates to embodiment 1) to 5), 8), 9) or 15) to 42) in any one compound, wherein
R 5represent (C 1-C 4) fluoroalkyl, halogen, cyano group, the aryl be optionally substituted or be optionally substituted heteroaryl (and be preferably trifluoromethyl, fluorine, chlorine, bromine, cyano group, 4-fluorophenyl, [1,2,3] triazol-1-yl or [1,2,3] triazole-2-base);
And the salt of these compounds (especially pharmaceutically acceptable salt).
45) another embodiment of the present invention relates to embodiment 1) to 6), 8) to 13) or 15) to 42) in any one compound, wherein
R 5represent halogen or cyano group (and being preferably fluorine, chlorine or cyano group);
And the salt of these compounds (especially pharmaceutically acceptable salt).
46) another embodiment of the present invention relates to embodiment 1) to 42) in any one compound, wherein
R 5represent halogen (and being preferably fluorine or chlorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
47) another embodiment of the present invention relates to embodiment 1) to 5), 8) to 10) or 15) to 42) in any one compound, wherein
R 5represent the aryl be optionally substituted or the heteroaryl be optionally substituted (and being preferably 4-fluorophenyl, [1,2,3] triazol-1-yl or [1,2,3] triazole-2-base);
And the salt of these compounds (especially pharmaceutically acceptable salt).
48) another embodiment of the present invention relates to embodiment 1) to 47) in any one compound, wherein
R 5and R 6in at least one be not hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
49) another embodiment of the present invention relates to embodiment 1) to 3), 8) or 15) to 42) in any one compound, wherein
R 5represent hydrogen; And
R 6represent halogen (and being preferably fluorine);
And the salt of these compounds (especially pharmaceutically acceptable salt).
50) another embodiment of the present invention relates to embodiment 1) to 48) in any one compound, wherein
R 6represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
51) another embodiment of the present invention relates to embodiment 1) to 50) in any one compound, wherein
R 7represent hydrogen;
And the salt of these compounds (especially pharmaceutically acceptable salt).
52) another embodiment of the present invention relates to embodiment 1), 3) to 5), 7) to 11), 13) or 15) to 51) in any one compound, wherein
R 10represent-C (O) OH ,-C (O) NH-S (O) 2cF 3or the heteroaryl be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
53) another embodiment of the present invention relates to embodiment 1), 3) to 5), 7) to 11), 13) or 15) to 51) in any one compound, wherein
R 10the heteroaryl representing-C (O) OH or be optionally substituted;
And the salt of these compounds (especially pharmaceutically acceptable salt).
54) another embodiment of the present invention relates to embodiment 1) to 51) in any one compound, wherein
R 10represent-C (O) OH;
And the salt of these compounds (especially pharmaceutically acceptable salt).
55) another embodiment of the present invention relates to embodiment 1) to 54) in any one compound, wherein the absolute configuration of Stereocenter is such as formula (I st1) described in
And the salt of these compounds (especially pharmaceutically acceptable salt).
56) another embodiment of the present invention relates to embodiment 1) to 54) in any one compound, wherein the absolute configuration of Stereocenter is such as formula (I st2) described in
And the salt of these compounds (especially pharmaceutically acceptable salt).
57) as embodiment 1) in preferred formula (I) compound that defines be selected from by the following group formed:
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((S)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(2-Carboxvmethoxv-5-methylphenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the bromo-2-carboxymethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
The bromo-1-of 7-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-4,5-difluorophenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
The bromo-1-of 5-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((R)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(5-bromo-2-carboxymethoxy-phenyl)-6,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-6,7-bis-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((R)-1-carboxyl-oxyethyl group)-5-cvano-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5,6-bis-;
1-(2-Carboxvmethoxv-5-dimethylsulfamoyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5-;
1-(2-Carboxvmethoxv-5-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-isopropyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(6-Carboxvmethoxv-benzo [1,3] dioxole-5-base)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-methoxyl group-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(2-Carboxvmethoxv-5-cvano-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-[2-((R)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
(S)-1-[2-((S)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
{ the fluoro-2-of 4-[(S)-2-((instead)-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(2-Carboxvmethoxv-5-cvano-phenyl)-5-;
1-(2-Carboxvmethoxv-3,5-difluorophenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methoxyl group-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-methoxyl group-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Chloro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of the bromo-1-of 5-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5,7-bis-;
2-[2-(2-benzo [d] isoxazole-3-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-naphthalene-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-quinoline-7-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-quinoline-6-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(2-{2-[3-(1-Ethyl-2-Methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(2,6-Dichloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[3-(the fluoro-phenoxy group of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[the fluoro-2-of 4-(2-{2-[4-(5-methyl-tetrazole-1-base)-phenyl]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
(2-{2-[3-(the chloro-3-oxo of 6--2,3-dihydros-benzo [Isosorbide-5-Nitrae] oxazine-4-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-methYl-thiazol-4-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ 2-[2-(2-benzo [b] thiene-3-yl--ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(3-benzothiazole-2-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(2-biphenyl-4-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(2-indoles-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-1H-benzimidazolyl-2 radicals-Ji-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(2-1,3-DIHYDRO-ISOINDOL-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
(the fluoro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(2-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-cyclopropyl-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2H-chromene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-Methoxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-phenyl of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(2-indoles-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(2-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(1,2,3,4-tetrahydrochysene-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzoglyoxaline-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the chloro-phenoxy group of-4-}-acetic acid;
{ the chloro-2-of 4-[2-(2-3,4-dihydro-2H-quinoline-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-indazole-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(3-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-trans-[2-(the chloro-phenyl of 2-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-phenyl-1H-imidazoles-2-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4-oxo-2-Phenyl-thiazol alkane-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[the chloro-2-of 4-(2-{3-[3-(2,3-Dimethvl-phenyl)-3H-imidazol-4 yl]-propionyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
(2-{2-[2-(biphenyl-2-base oxygen base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the chloro-phenoxy group of-4-)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-is to tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-phenoxy group of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(2-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-1H-indol-3-yl of 5-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(6-Mehtoxy-Benzofuran-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 4-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between 3-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-phenoxy group of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-1H-indol-3-yl of 5-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(4-p-methylphenyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzo of 5-[b] thiene-3-yl-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-1H-indoles-2-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methyl-benzo [d] isoxazole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-benzo [d] isoxazole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 4-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzyloxy-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the chloro-phenoxy group of-4-}-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 3-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(2,3-Dichloro-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between 4-tolyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(4-o-tolyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 3-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(3-methoxyl group-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of 2-(2-benzyloxy-ethanoyl)-5-] the chloro-phenoxy group of-4-}-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-5-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-phenyl-propioloyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
[the fluoro-2-of 4-(2-phenyl acetyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the fluoro-2-of 4-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzyloxy-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[3-(2-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(3-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(4-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
{ the fluoro-2-of 4-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-naphthalene-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-oxy-o-cresyl-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[2-(1-Methyl-1H-indole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(the chloro-phenoxy group of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[3-(the fluoro-phenyl of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-(2-indane-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[(E)-3-(the fluoro-phenyl of 2-)-acryl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-((E)-3-o-tolyl-acryl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(5-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(3-phenoxy group-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[3-(4-Methanesulfonyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ 2-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-oxy-o-cresyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-phenoxy group of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[4-(2-methoxyl group-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the chloro-2-{2-of 4-[(instead)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-((instead)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[(instead)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the chloro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2,4-Dichloro-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2-methoxyl group-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-phenyl-3H-[1,2,3] triazole-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(3-phenyl-3H-[1,2,3] triazole-4-yl sulfenyl)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,2-dimethyl-propyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-butyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-phenyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-phenyl formate;
The chloro-phenyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-tetryl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-ethyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methoxy-phenyl ester;
(S) the chloro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of 2-)-ethyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of 2-)-ethyl ester;
The chloro-phenyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
Fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of the 2-)-ethyl esters of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-ethanesulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-Methanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(5-benzenesulfonyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-ethanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methane sulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-ethanesulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
5-benzenesulfonyl-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-pyrimidine-5-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(the fluoro-biphenyl of 4-Carboxvmethoxv-4'--3-base)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(2-{2-[2-(the chloro-benzyloxy of 3-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[2-(the chloro-benzyloxy of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(3-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(4-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(3-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(4-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(1-methyl isophthalic acid H-pyrazole-3-yl methoxyl group)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[2-(2-benzyl carbamyl-1,2,3,4-tetrahydro-isoquinoline-1-base) the fluoro-phenoxy group of-4-]-acetic acid;
[the fluoro-2-of 4-(2-phenethyl-carbamoyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the fluoro-2-of 4-[2-(2-methyoxy-benzyl carbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-methyoxy-benzyl carbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(the chloro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
(2-{2-[2-(the chloro-phenyl of 2-)-ethyl carbamyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
{ 2-[2-(2-BENZENESUFONYLAMINO-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
(2-{2-[2-(3,5-dimethyl-isoxazole-4-sulfuryl amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-BENZENESUFONYLAMINO of 3-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-BENZENESUFONYLAMINO of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(3,4-Difluoro-benzenesulfonyl is amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[2-(N-benzenesulfonyl-N-Methyl-amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
[the fluoro-2-of 4-(2-{2-[N-(the fluoro-benzenesulfonyl of 3-)-N-Methyl-amino]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
[2-(2-{2-[N-(3,4-Difluoro-benzenesulfonyl)-N-Methyl-amino]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases) the fluoro-phenoxy group of-4-]-acetic acid;
1-(5-carbamyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-Carboxvmethoxv-5-(5-sulfo--4,5-dihydro-[and 1,2,4] oxadiazole-3-bases)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-4-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-6-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-(3-carboxyl-propoxy-) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
{ 4-cyano group-2-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
1-(2-Carboxvmethoxv-5-cvano-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(R)-1-[2-(1-carboxyl-oxyethyl group) the chloro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-[1,2,3] triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-[1,2,3] triazole-2-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate; And
{ the chloro-2-of 4-[2-(2-methyoxy-benzyl thiocarbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
Or the salt of these compounds (especially pharmaceutically acceptable salt);
Should be appreciated that, for any one in the compound enumerated above, not specially appointed Stereocenter can be definitely (R)-configuration or definitely (S)-configuration, and not specially appointed double bond can be (E)-configuration or (Z)-configuration; The Stereocenter being such as in 1 position of 1,2,3,4-tetrahydroisoquinoline nuclear structure can be definitely (R)-configuration or definitely (S)-configuration (and preferably in absolute (S)-configuration).It should be noted that the compound containing more than one Stereocenter can in definitely (R)-or definitely (S)-configuration at not specially appointed each Stereocenter, such as { the fluoro-2-of 4-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydro-isoquinoline-1-base]-phenoxy group } compound cited by-acetic acid can be the fluoro-2-of 2-{4-[(S)-2-((1R, 2R)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid, the fluoro-2-of 2-{4-[(S)-2-((1S, 2S)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid, the fluoro-2-of 2-{4-[(R)-2-((1R, 2R)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid, the fluoro-2-of 2-{4-[(R)-2-((1S, 2S)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid or its mixture (and be preferably the fluoro-2-of 2-{4-[(S)-2-((1R, 2R)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid or the fluoro-2-of 2-{4-[(S)-2-((1S, 2S)-2-phenyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydroisoquinoline-1-base]-phenoxy group }-acetic acid).
58) as embodiment 1) in other preferred formula (I) compound that defines be selected from by the following group formed:
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
The bromo-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate;
{ the chloro-2-of 4-[(S)-2-((1R, 2R)-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-trifluoromethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-trifluoromethyl-benzyl ester;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-bis-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-dimethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-dimethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethyl-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4,6-trimethylammoniums-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-6-of dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethyl-pyridin-3-yl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-cyano group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-2-of dihydro-1H-isoquinoline 99.9-2-formic acid 5-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-5-of dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-acid cyclohexyl base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-pyrazole-3-yl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid cyclopentyl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-tetryl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-butyl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-ethyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid cyclopropyl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3,5-Dimethyl-pyrazol-1-base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methyl-isoxazole-3-base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1,5-dimethyl-1H-pyrazole-3-yl methyl esters;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-Ji)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3,5-dimethyl-isoxazole-4-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-5-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formate;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of 3-)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-dimethyl-2H-pyrazole-3-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-base)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [d] isoxazole-3-base methyl esters;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-the Ji)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3, the 5-dimethyl-isoxazole-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of the 3-)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2, the 5-dimethyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl) of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis--ethyl ester;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-the base)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [d] the isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-the Ji)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of the 3-)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2, the 5-dimethyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl) of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6--ethyl ester;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-the base)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [the d] isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxyl group-benzyl ester;
(S) the fluoro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-trifluoromethyl-benzyl ester;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-7-;
1-(2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(the chloro-2-{2-of 4-[3-(the fluoro-3-Methvl-indole of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-methoxyl group-pyrrolo-[2,3-b] pyridine-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4,6-dimethoxy-pyrrolo-[2,3-b] pyridine-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4,6-dimethoxy-indoles-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-indoles-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indoles of 7--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-pyrrolo-[3,2-b] pyridine-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(4-Methoxv-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indazole of 3--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-Methvl-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indoles of 6--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 4--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 6--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-Methoxv-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{ of 4-(S)-6-[3-(the fluoro-indazole of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{ of 4-(S)-6-[3-(3-methyl-indazol-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[3-(the chloro-indazole of 6--1-base)-propionyl] fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of-6-}-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-pyrrolo-of 3-[2,3-b] pyrazine-5-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(2-Difluoro-phenoxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-phenoxy group of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(quinoline-8-yl oxygen base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-phenoxy group of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(trans-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(3-methoxyl group-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between trans-2-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-phenyl of trans-2-)-cyclopropyl carbonyl]-6-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(trans-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl] fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of-6-}-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[4-(the fluoro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-6-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(3-Methvl-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-indazole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-3,4-dihydro-2H-quinoline-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(2,4-Dimehtyl-phenoxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2,2-dimethyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the chloro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 3-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
[2-(2-benzyl carbamyl-1,2,3,4-tetrahydro-isoquinoline-1-base) the chloro-phenoxy group of-4-]-acetic acid;
[the chloro-2-of 4-(2-phenethyl-carbamoyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 4-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4-;
{ the chloro-2-of 4-[2-trans-(2-phenyl-cyclopropyl carbonyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-phenoxy group of 4-)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(quinoline-8-yl oxygen base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-indazole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-benzo [d] isoxazole-3-base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-Methvl-indole-1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 2-)-propionyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-trans-[2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-trans-[2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-indazole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 5--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-3-methyl-indazol of 4--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-3-methyl-indazol of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-3-methyl-indazol of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-methyl-indazol-1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 4--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 7--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 2-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 3-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 4-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
[2-(2-benzyl carbamyl-2,3-dihydro-1H-isoindole-1-base) the chloro-phenoxy group of-4-]-acetic acid;
[the chloro-2-of 4-(2-phenethyl-carbamoyl-2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-acetic acid;
{ the chloro-2-of 4-[2-(the chloro-benzyl carbamyl of 2-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
Chloro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,5-bis-;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,5-bis-;
{ the chloro-2-of 4-[(S)-2-((1R, 2R)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(S)-1-[the chloro-2-of 5-(2-oxo-2-trifluoromethanesulphonylamino-oxyethyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
(S)-1-[the chloro-2-of 5-(5-oxo-4,5-dihydro-[1,3,4] oxadiazole-2-ylmethoxies)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates; And
1-[the chloro-2-of 5-(3-hydroxyl-isoxazole-5-base methoxyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Or the salt of these compounds (especially pharmaceutically acceptable salt);
Should be appreciated that, for any one in the compound enumerated above, not specially appointed Stereocenter can be definitely (R)-configuration or definitely (S)-configuration, and not specially appointed double bond can be (E)-configuration or (Z)-configuration; The Stereocenter being such as in 1 position of 1,2,3,4-tetrahydroisoquinoline or isoindoline nuclear structure can be definitely (R)-configuration or definitely (S)-configuration (and preferably in absolute (S)-configuration).It should be noted that the compound containing more than one Stereocenter can in definitely (R)-configuration or definitely (S)-configuration at not specially appointed each Stereocenter, such as (trans-[2-(the fluoro-phenyl of the 2-)-cyclopropyl carbonyl]-2 of the chloro-2-{2-of 4-, 3-dihydro-1H-isoindole-1-base }-phenoxy group) compound cited by-acetic acid can be (the chloro-2-{ of 4-(S)-2-[(1S, 2S)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid, (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid, (the chloro-2-{ of 4-(R)-2-[(1S, 2S)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid, (the chloro-2-{ of 4-(R)-2-[(1R, 2R)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid or its mixture (and be preferably (the chloro-2-{ of 4-(S)-2-[(1S, 2S)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid or (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2, 3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid).
Unless expressly specified otherwise, otherwise in the context of the present invention in context, generic term used and title preferably have following implication:
When compound, salt, medical composition, disease and analogue thereof use plural form, this is intended to also mean individualized compound, salt, medical composition, disease or its analogue.
Term " pharmaceutically acceptable salt " refers to non-toxic inorganic or organic acid and/or base addition salt.Can referring to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
Embodiment 1) to 58) in any one formula (I) compound or its pharmaceutically acceptable salt can be used for preparing medicament and be applicable to prevention and/or treatment is selected from by the disease of the following group formed: chronic and acute allergic/Immunological diseases/illness, comprise asthma, allergic asthma, addicted to Yihong blood cell asthma, severe asthma, rhinitis, allergic rhinitis, angioedema, insect venom allergies, drug allergy, allergic sinusitis, allergic nephritis, anaphylaxis conjunctivitis, atopic dermatitis, bronchial asthma, food anaphylaxis, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory enteropathy and rheumatoid arthritis, addicted to Yihong blood cell relative disease, comprise polyangitis, as Xie Ge-Si Tuosi syndrome (Churg-Strauss syndrome), Wei Genashi granuloma (Wegener's granulomatosis), microscopic Polyangiitis (and the microscopic Polyangiitis of organ specificity), waits group addicted to her erythrocytosis, as addicted to Yihong blood cell pneumonia, addicted to Yihong blood cell esophagitis, reflux esophagitis, addicted to Yihong blood cell endocarditis (Lv Foleshi endocarditis (Loeffler'sendocarditis)), addicted to her erythrocytosis-myalgia syndrome, addicted to Yihong blood cell fascitis, addicted to Yihong blood cell pustule type folliculitis (too Teng Shi disease (Ofuji ' s disease)), addicted to Yihong blood cell ulcer, ALH is concurrent addicted to her erythrocytosis (ALHE), addicted to Yihong blood cell cellulitis (Wei Ersi syndrome (Wells syndrome)), chronic addicted to Yihong blood cell leukemia and DRESS syndrome (drug eruption is concurrent addicted to her erythrocytosis and systemic symptoms), and basophilia blood cell relative disease, comprise Basophilic leukemia and basophilia leukocytosis disease.
In a preferred embodiment, embodiment 1) to 58) in any one formula (I) compound or its pharmaceutically acceptable salt can be used for preparing medicament and be applicable to prevention and/or treatment is selected from by the disease of the following group formed: asthma, allergic asthma, addicted to Yihong blood cell asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergies, drug allergy, allergic sinusitis, allergic nephritis, anaphylaxis conjunctivitis, atopic dermatitis, food anaphylaxis, systemic mast cell disorders, anaphylactic shock, urticaria and eczema.
In another preferred embodiment, embodiment 1) to 58) in any one formula (I) compound or its pharmaceutically acceptable salt can be used for preparing medicament and be applicable to prevention and/or treatment is selected from by the disease of the following group formed: addicted to Yihong blood cell relative disease, comprise polyangitis, as Xie Ge-Si Tuosi syndrome, Wei Genashi granuloma, microscopic Polyangiitis (and the microscopic Polyangiitis of organ specificity), waits group addicted to her erythrocytosis, as addicted to Yihong blood cell pneumonia, addicted to Yihong blood cell esophagitis, reflux esophagitis, addicted to Yihong blood cell endocarditis (Lv Foleshi endocarditis), addicted to her erythrocytosis-myalgia syndrome, addicted to Yihong blood cell fascitis, addicted to Yihong blood cell pustule type folliculitis (too Teng Shi is sick), addicted to Yihong blood cell ulcer, ALH is concurrent addicted to her erythrocytosis (ALHE), addicted to Yihong blood cell cellulitis (Wei Ersi syndrome), chronic addicted to Yihong blood cell leukemia and DRESS syndrome (drug eruption is concurrent addicted to her erythrocytosis and systemic symptoms).
In another preferred embodiment, embodiment 1) to 58) in any one formula (I) compound or its pharmaceutically acceptable salt can be used for preparing medicament and be applicable to prevention and/or treatment is selected from by the disease of the following group formed: basophilia blood cell relative disease, it comprises Basophilic leukemia and basophilia leukocytosis disease.
The present invention also relates to embodiment 1) to 58) in any one the purposes of formula (I) compound, it is for the preparation of in order to treatment and/or the medical composition preventing disease mentioned above.
The present invention also relates to embodiment 1) to 58) in any one the pharmaceutically acceptable salt of formula (I) compound and medical composition thereof and pharmaceutical preparation.
Medical composition of the present invention contains at least one embodiment 1) to 58) in any one formula (I) compound (or its pharmaceutically acceptable salt) optional containing carrier and/or thinner and/or adjuvant as promoting agent.
Embodiment 1) to 58) in any one formula (I) compound and pharmaceutically acceptable salt thereof can be used as medicament, such as, in for the medical composition form through intestines (such as especially oral) or parenteral (comprising topical application or suction) administration.
Can according to mode well-known to those skilled in the art (see such as Remington, The Science andPractice of Pharmacy, 21st edition (2005), 5th part, " PharmaceuticalManufacturing " [being published by Lippincott Williams & Wilkins]), by by described formula (I) compound or its pharmaceutically acceptable salt, optional and other have the combinations of substances of therapeutic value, form galenical administration form (galenical administration form) and prepare medical composition together with inert solid compatible in the treatment be applicable to or liquid carrier material and (if desired) conventional pharmaceutical adjuvants.
The present invention also relates to a kind of method of prevention or the disease mentioned by treatment herein or illness, and the method comprises the embodiment 1 giving medicinal activity amount to individuality) to 58) in any one formula (I) compound or its pharmaceutically acceptable salt.
The present invention also comprises isotopic labeling, especially 2formula (I) compound that H (deuterium) marks, except one or more atom is respectively through ordination number is identical but atomic mass is different from except the atomic substitutions of the common atomic mass of occurring in nature in this compound, these compounds and formula (I) Compound Phase with.Isotopic labeling, especially 2formula (I) compound that H (deuterium) marks and salt thereof are in category of the present invention.Use higher isotope 2h (deuterium) replaces hydrogen can produce comparatively greater metabolic stability, thus such as extends vivo half-life or reduce required dosage, maybe can reduce the inhibition to cytochrome P 450 enzymes, thus improve such as safe kenel.In one embodiment of the present invention, formula (I) compound is without isotopic labeling, or it only marks through one or more D atom.In a sub-embodiment, formula (I) compound is completely without isotopic labeling.Can be similar to method hereinafter described through isotope-labeled formula (I) compound, but prepared by the applicable reagent using suitable isotropic substance to change or initial substance.
Suitably and suitable time, any formula (I), formula (I mentioned herein sT1), formula (I sT2), formula (I p), formula (I-1), formula (I-2), formula (I-3), formula (I iSO) or formula (I tET) compound is all interpreted as the salt (and especially pharmaceutically acceptable salt) also mentioning these compounds.Certainly, when doing necessary correction, formula (I is applicable to the prioritizing selection that formula (I) compound is pointed out sT1) compound, formula (I sT2) compound, formula (I p) compound, formula (I-1) compound, formula (I-2) compound, formula (I-3) compound, formula (I iSO) compound and formula (I tET) compound and formula (I), formula (I sT1), formula (I sT2), formula (I p), formula (I-1), formula (I-2), formula (I-3), formula (I iSO) and formula (I tET) salt of compound and pharmaceutically acceptable salt.Be equally applicable to as these compounds of medicament, containing these compounds as the medical composition of activeconstituents or these compounds purposes for the manufacture of the medicament in order to treat disease of the present invention.
Unless for illustration of temperature, otherwise the term " about " (or " approximately ") be placed in subject application before numerical value " X " refers to that 10% to X that X deducts X adds the interval of 10% of X, and preferably refers to that 5% to X that X deducts X adds the interval of 5% of X.For under the particular case of temperature, the term " about " (or " approximately ") be placed in this application before temperature " Y " refers to that temperature Y deducts 10 DEG C to add 10 DEG C interval to Y, and preferably refers to that Y deducts 5 DEG C to add 5 DEG C interval to Y.In addition (r.t.) refers to the temperature of about 25 DEG C, as used herein, the term " room temperature ".
When use word " ... between " describe numerical range time, should be appreciated that the end points of shown scope is clearly included within the scope of this.For example: if temperature range is described as between 40 DEG C and 80 DEG C, then this mean end points 40 DEG C and 80 DEG C be included within the scope of this, if or variable-definition be integer between 1 and 4, then this means this variable is integer 1,2,3 or 4.
As discussed previously, formula (I) compound regulates the PGD of CRTH2 acceptor 2activation.The biological action of these compounds can be tested in multiple in vitro, in vitro and in vivo calibrating.Formula (I) compound (can be respectively the people such as Arimura A., J.Pharmacol.Exp.Ther.2001,298 (2), 411-419 by being similar to described in document in conjunction with the ability of CRTH2 acceptor; And the people such as Sawyer N., Br.J.Pharmacol, 2002,137,1163-1172) method and measure by the calibrating hereafter described in experimental section.
Another aspect of the invention is the method for a kind of preparation formula (I) compound.Formula of the present invention (I) compound can be prepared according to the reaction sequence described in following flow process, wherein X, Y, Z, n, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9and R 10defined such as formula (I).Other abbreviations used are defined at experimental section.In some cases, common moiety X, Y, Z, n, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9and R 10may be incompatible with the combination shown in following flow process, and therefore need to use protecting group (PG).For example, the reactive functional group of such as hydroxyl, amino, imido grpup, sulfenyl or carboxyl (if these groups are desired in final product) may must be protected undesirably to participate in reaction to avoid it.The use of protecting group is at (see such as " ProtectiveGroups in Organic Synthesis ", T.W.Greene, P.G.M.Wuts, Wiley-Interscience, 1999) well known in the art.Assuming that these protecting groups are in appropriate location if desired.In hereafter specification sheets, such as " PG " as preferably referring to such as tertbutyloxycarbonyl, carbobenzoxy-(Cbz) or allyloxycarbonyl during amino protecting group, the most preferably group of carbobenzoxy-(Cbz).In addition, " L " refers to leaving group, (as such as Mitsunobu reacts, (light prolongs reaction to the hydroxyl of such as activity hydroxy (such as methylsulfonic acid ester group, toluenesulphonic acids ester group, active ester etc.), in-situ activation, Mitsunobu reaction) middle employee), or halogen, especially chlorine or bromine.In addition, " R " refers to (C 1-C 4) alkyl, preferable methyl, ethyl or the tertiary butyl.
Generally speaking, all chemical conversions can according to described in such as document or as known standard method to perform described in hereafter program.Can also known mode itself be its pharmaceutically acceptable salt by obtained converting compounds.
Generally speaking, R 10formula (I) compound of expression-COOH is that (wherein R represents (C by the ester of structure 1 1-C 4) alkyl (being preferably methyl, ethyl or the tertiary butyl)) obtain by use conventional procedure hydrolysis ester group, such as by the intermediate (wherein R represents methyl or ethyl) of whipped-up structure 1 and the aqueous solution of LiOH, NaOH or KOH in the organic cosolvent (organic co-solvent) of such as alcohol (as MeOH or EtOH), THF, acetone, MeCN or DMF; Or by whipped-up structure 1 in the acid of such as TFA intermediate (wherein R represents the tertiary butyl) and obtain.
Structure 1, wherein R represents (C 1-C 4) alkyl
The intermediate of structure 1 is such as by making the intermediate of structure 2 or its salt (such as hydrochloride) and formula L-C (O) X-R 1reagent (wherein X and R 1be such as formula (I) to define and L is the leaving group of such as halogen (especially chlorine)) at such as NEt 3, DIPEA, N-ethyl-morpholine, N-methyl piperidine or pyridine alkali exist under reaction and obtaining in the applicable solvent of such as THF or DCM.Initial substance L-C (O) X-R 1can be chloro-formic ester; Acetyl anhydride; Or acyl halide, as acyl chlorides or acylbromide.Acyl halide can be buied, be known in the art or can by corresponding buy or know carboxylic acid to react under condition well known by persons skilled in the art with the halogenating agent as oxalyl chloride or Phosphorus Oxychloride and obtain on the spot.
Structure 2
In another aspect, make the intermediate of structure 2 and can buy or know isocyanic ester or lsothiocyanates reacts in the presence of a base, form the intermediate of structure 1.
In another aspect, with the intermediate of triphosgene, CDI or its analogue activatable structural 2, then with alcohol or amine processing reaction intermediate, obtain the intermediate of structure 1, wherein X represents-NH-or-O-
In another aspect, structure 2 intermediate with can buy or know the coupling reagent of carboxylic acid at such as EDC, TBTU, DIC, HATU, DCC, Grignard reagent (Ghosez's reagent) or its analogue exist under at such as NEt 3, DIPEA or pyridine alkali there is the intermediate that lower condensation forms structure 1.
In another aspect, make the intermediate of structure 2 and bromoacetyl bromide at such as NEt 3or be obtained by reacting bromide 3 under the alkali existence of DIPEA, then use it for and alcohol R aoH (wherein R arepresent the aryl-(C be optionally substituted 1-C 2) alkyl or heteroaryl-(C of being optionally substituted 1-C 2) alkyl) under the alkali of such as sodium hydride exists, carry out etherification reaction, obtain the compound (flow process 1) of structure 1-A.Or, the intermediate of structure 2 is used for carry out acid amides coupling with N protected amino acid, obtains acid amides 4.Remove protecting group (such as catalytic hydrogenolysis Cbz protecting group), gained amine and SULPHURYL CHLORIDE R afterwards bsO 2cl (wherein R brepresent the aryl be optionally substituted or the heteroaryl be optionally substituted) react the derivative producing structure 1-B.Gained sulphonamide with Me-L (wherein L is bromine or iodine) alkylation under the alkali of such as sodium hydride exists, can obtain the intermediate (flow process 2) of structure 1-C.
The synthesis of the intermediate of flow process 2. structure 1-B and 1-C.
In another aspect, intermediate and carbonic ether 5 (the wherein R of structure 2 is made crepresent the aryl that is optionally substituted) at such as NEt 3or there is lower reaction in the alkali of DIPEA, obtains the intermediate (flow process 3) of structure 1-D.Carbonic ether 5 be by make phenylcarbinol 6 and carbonic acid N, N'-bis-succimide ester react under the alkali of such as DMAP exists and prepare.
The synthesis of the intermediate of flow process 3. structure 1-D.
Or, make the intermediate of structure 2 and chloroformic acid 4-nitro phenyl ester at such as NEt 3or there is lower condensation in the alkali of DIPEA, obtains carbamate 7 (flow process 4).Then under potassium tert.-butoxide exists, alcohol R is used eoH (wherein R erepresent (C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted) process carbamate 7, obtain the compound of formula (I-A).Under these specified conditions, between the same reaction period, there is saponification and substitution reaction.
The synthesis of the compound of flow process 4. formula (I-A).
In another alternative aspect, at such as NEt 3or obtain ethernamine 8 (flow process 5) with the intermediate of acrylate chloride process structure 2 under the alkali existence of DIPEA.Ethernamine 8 can with R gthere is Michael addition (Michael addition) in H (9), wherein R gh represents the heteroaryl be optionally substituted containing hydrogenation nitrogen-atoms in loop systems, as the indoles, azaindole or the indazole derivatives that are optionally substituted.This reaction can perform under Potassium monofluoride/aluminum oxide exists people such as (, Lett.Org.Chem.2006,3,157-160) F.M.Moghaddam and carry out on the nitrogen-atoms of heteroaryl, obtains the compound of formula (I-B).Under these special reaction condition, between the same reaction period, produce potassium hydroxide and Michael addition and saponification reaction occur.
The synthesis of the intermediate of flow process 5. formula (I-B).
The intermediate of structure 2 obtains after the intermediate of application reaction conditions self-structure 10 well known by persons skilled in the art removes protecting group (PG).PG is preferably the group of such as tertbutyloxycarbonyl or carbobenzoxy-(Cbz).Benzyloxycarbonyl protecting group is removed by hydrogenolysis or with acid treatment; Make tertbutyloxycarbonyl cracking in acid condition.
Structure 10
N represents that the intermediate (tetrahydroisoquinoline) of the structure 10 of 1 obtains by a kind of synthesis path hereinafter described.For example, the intermolecular α-amido alkyl between 3,4-dihydro-isoquinoline 11 and phenol 12 turns use (flow process 6) into and obtains tetrahydroisoquinoline 13.In this reaction, 3,4-dihydro-isoquinoline 11 first at room temperature activates with the protecting group precursor PGL of such as tert-Butyl dicarbonate or chloro-formic ester (as chloroformic acid benzyl ester) in MeCN.Gained active substance replaces through electron rich aromatic substance (such as phenol 12) electrophilic under about 60 DEG C to the temperature of 80 DEG C in MeCN.Phenol 13 is through electrophilic reagent L-Y-CO subsequently 2r (wherein Y be such as formula in (I) to define and L is leaving group, such as bromine) at such as Cs 2cO 3or K 2cO 3alkali there is the intermediate (n=1) that lower alkylation obtains structure 10.
The synthesis of the intermediate (n=1) of flow process 6. structure 10.
In another aspect, with the protecting group precursor PG of such as tert-Butyl dicarbonate or chloro-formic ester (as chloroformic acid benzyl ester) 1l process dihydro-isoquinoline 11, adds grignard Grignard reagent (Grignardreagent) 14 afterwards, obtains tetrahydroisoquinoline 15 (flow process 3).Grignard reagent 14 prepares by with the solution-treated bromide 16 of isopropyl-magnesium chloride/lithium chloride mixture.Compound 16 via with allyl halide (such as allyl bromide 98) or benzyl halide (such as bromotoluene) as protecting group precursor PG 2l is at such as K 2cO 3alkali exist under in the solvent of such as acetone, protect phenol 17 to obtain.The phenol protecting group of selectively removing structure 15, as at carbamate groups protecting group (PG 1) there is lower Pd (PPh 3) 4and barbituric acid (barbituric acid) derivatives selectively removes allyl group, uses electrophilic reagent L-Y-CO subsequently 2r (wherein Y be such as formula (I) to define and L is the leaving group of such as bromine) at such as Cs 2cO 3or K 2cO 3alkali exist under carry out alkylation and produce the intermediate of structure 10-A.
The synthesis of the intermediate of flow process 7. structure 10-A.
In another aspect, bromide 18 and boric acid R 5b (OH) 2the intermediate that suzuki reaction (Suzuki reaction) obtains structure 10-B is there is under palladium catalyst exists.Bromide 18 also can be used in your cross-coupling reaction (Stille cross-coupling reaction) of history Supreme Being.Bromide 18 also can use-sulfinate derivative R is (O) ONa (wherein R irepresent (C 1-C 4) alkyl or phenyl) copper catalyst at such as CuI and the ligand as proline ester be converted into the sulfone of structure 10-C under existing.Finally, bromide 18 can use the copper catalyst as CuI under the bidentate ligands of such as N, N'-dimethyl-1,2-cyclohexanediamine exists, be converted into the triazole derivative (flow process 8) of structure 10-D.
Or bromide 19 can use-sulfinate derivative R is (O) ONa (wherein R irepresent (C 1-C 4) alkyl or phenyl) copper catalyst at such as CuI and the ligand as proline ester be converted into the sulfone of structure 10-E under existing.Bromide 19 can use sulfone amide derivative R jsO 2nH 2(wherein R jrepresent (C 1-C 4) alkyl) under the copper catalyst of such as CuI exists, under the bidentate ligands of such as DMG exists, be converted into the sulphonamide (flow process 9) of structure 10-F.
The synthesis of the intermediate of flow process 8. structure 10-B, 10-C and 10-D.
The synthesis of the intermediate of flow process 9. structure 10-E and 10-F.
In another aspect, the sequence (R described in flow process 6 can be followed 5=CN) nitrile 20 that obtains uses water and the platinum catalyst developed by the people such as Ghaffar (Tet.Lett.1995,36,8657) to be converted into the acid amides of structure 10-G by nitrile hydrolysis.Or, nitrile 20 by with azanol and thiocarbonyldiimidazole condensation Zhuanization Wei oxadiazole derivative (flow process 10).
The synthesis of the intermediate of flow process 10. structure 10-G and 10-H.
Required 3,4-dihydro-isoquinoline 11 uses the Bischler-Na Pila Bielski of improvement to react (Bischler-Napieralski reaction) by corresponding phenylethylamine 21 (or corresponding hydrochloride) to prepare (flow process 11).Therefore, phenylethylamine 21 and ethyl formate are obtained by reacting corresponding methane amide, its Zhuanization Wei oxazole intermediate when processing with oxalyl chloride and iron(ic) chloride (III).With methyl alcohol Chu Li oxazole and derivative obtains 3,4-required dihydro-isoquinolines 11 under the acid of such as sulfuric acid exists.If can not buy, then phenylethylamine 21 can synthesize by reduction corresponding α, β-unsaturated nitro-derivative 22, and α, β-unsaturated nitro-derivative 22 is prepared via Henle reaction (Henry reaction) by aldehyde 23.Or, R 7represent that the phenylethylamine 21 of methyl use methyl iodide dialkyl, afterwards with the acquisition of Lithium aluminum hydride reduction nitrile under being existed via the alkali at such as sodium hydroxide by corresponding benzyl cyanide 24.Finally, dihydro-isoquinoline 11 can by being oxidized corresponding tetrahydroisoquinoline 25 with N-bromo-succinimide, basic treatment obtains (flow process 11) afterwards.
The synthesis of flow process 11. dihydro-isoquinoline 11.
N represents that the intermediate (isoindoline) of the structure 10 of 0 can be prepared as described in flow process 12.Bromizate the lithium halogen exchange that thing 26 occurs to be mediated by nBuLi, and the process of gained lithiumation material sulfinyl amine 27 obtains isoindoline 28.Sulfinyl amine auxiliary agent is (such as under HCl exists) cracking then in acid condition, and the gained amine protecting group precursor PG of such as tert-Butyl dicarbonate or chloro-formic ester (as chloroformic acid benzyl ester) 1l process, obtains isoindoline 29.The phenol protecting group of selectively removing structure 29, as at carbamate groups protecting group (PG 1) there is lower Pd (PPh 3) 4and barbituric acid derivatives selectivity removes allyl group, obtain phenol 30.Compound 30 is at such as Cs 2cO 3or K 2cO 3alkali exist under through electrophilic reagent L-Y-CO 2r (wherein Y be such as formula in (I) to define and L is leaving group, such as bromine) alkylation obtains the intermediate of structure 10-J.Compound 27 is via with allyl halide (such as PG by salicylaldehyde derivatives 31 2l=chlorallylene) or benzyl halide (such as PG 2l=bromotoluene) protect phenol moieties to prepare under the alkali of such as salt of wormwood exists in the solvent of such as DMF.Aldehyde 32 is at Ti (OEt) 4in the solvent of such as THF, use t-butyl sulfonamide process under existence, obtain sulfinyl amine 27.
The synthesis of the isoindoline of flow process 12. structure 10-J.
Required bromide 26 is prepared (flow process 13) via with thionyl chloride chlorination by corresponding phenylcarbinol 33.If can not buy, then phenylcarbinol 33 uses such as sodium borohydride reduction corresponding aldehyde 34 to synthesize by the solvent of such as MeOH.Aldehyde 34 can be added DMF to prepare via with the highly basic deprotonation of such as LDA by corresponding bromide 35 subsequently.
The synthesis of flow process 13. bromide 26.
In another aspect, the carboxylic moiety of formula (I-C) compound can be replaced through bioelectricity isostere body.For example, carboxylic acid can under the alkali of the such as coupling reagent of TBTU and such as DIPEA exists with hydrazine coupling, obtain hydrazide intermediate 36.Then hydrazides 36 can at such as NEt 3alkali there is the lower cyclization that CDI mediation occurs, form 5-oxo-4,5-dihydro-[1,3,4] oxadiazole derivative (flow process 14) of formula (I-D).Or the acid amides coupling under the alkali of the such as coupling reagent of HATU and such as DIPEA exists between carboxylic moiety and trifluoromethanesulfonamide obtains the fluoroform sulfonamido derivative of formula (I-E).In another aspect, carboxylic moiety can at the coupler of such as HATU and as NEt 3alkali there is lower and cyanamide generation acid amides coupling, obtain the cyanogen aminoderivative (flow process 14) of formula (I-F).
The synthesis of the compound of flow process 14. formula (I-D), (I-E) and (I-F).
Or the ester of structure 1 can use aqueous hydroxylamine process in the solvent of such as Virahol, forms the hydroxamic acid ester (flow process 15) of formula (I-G).
The synthesis of flow process 15. formula (I-G) compound.
In another aspect, known alcohol 37 (people such as R.Riess, Eur.J.Org.Chem 1998,473-479) can by such as NEt 3alkali exist under be converted into methanesulfonates 38 with methylsulfonyl chloride process.Then under the alkali of such as salt of wormwood exists, methanesulfonates 38 alkylated benzenes amphyl 13 (n=1) or 30 (n=0) (flow process 16) are used.In acetic acid, produce intermediate 39 by the overall deprotection base of such as Hydrogen bromide mediation, it can follow a kind of description scheme 2 converting compounds is that the synthesis path (see above) of formula I is converted into formula (I-H) compound.
The synthesis of flow process 16. formula (I-H) compound.
Or phenol 13 (n=1) or the alkylation under the alkali of such as salt of wormwood exists of 30 (n=0) available chlorine acetonitrile, obtain carbonitrile derivatives 40 (flow process 17).Remove protecting group in acid condition and converting compounds as structure 2 is introduce required residue R as described in formula (I) compound 1-X-C (Z)-, obtain intermediate 41.Carbonitrile derivatives 41 can by the tetrazolium being converted into formula (I-J) with sodiumazide process.In different methods, compound 41 can under the alkali of such as salt of wormwood exists with azanol reaction.Can there is the cyclization of CDI mediation in gained N-hydroxy formamidine radical derivative 42, obtain 5-oxo-4,5-dihydro-[1,2,4] oxadiazole derivative of formula (I-K) under the alkali of such as DBU exists.
The synthesis of the compound of flow process 17. formula (I-J) and formula (I-K).
Acid derivative for carrying out acid amides coupling with the compound of structure 2 can buy, is known in the art or can obtains according to flow process 18 and 19.Bromo derivative 43 (wherein R kand R lrepresent hydrogen, (C independently 1-C 4) alkyl, (C 1-C 4) alkoxyl group, chlorine or fluorine) and zinc bromide derivative between root bank cross-coupling reaction (Negishi cross-coupling reaction) obtain ester 44, it becomes corresponding carboxylic acid 45 (flow process 18) through saponification.
The synthesis of flow process 18. acid derivative 45.
Or, R mand R nrepresent hydrogen, (C independently 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) styracin 46 of fluoroalkyl or halogen is converted into temperature and strangles primary amide (Weinreb amide) 47.In section-and tchaikovsky Cyclopropanated (Corey-Chaykovsky cyclopropanation) obtains cyclopropane 48, and its hydrolysis becomes corresponding carboxylic acid 49 (flow process 19).
The synthesis of flow process 19. acid derivative 49.
When obtaining formula (I) compound of the form of mixtures being enantiomer or diastereomer, enantiomer or diastereomer can use method known to those skilled in the art to be separated: such as by being formed and being separated diastereo-isomerism salt or carrying out HPLC:DaicelChiralPak AD-H (5 μm) tubing string by the chiral stationary phase below such as, Daicel ChiralCel OD-H (5 μm) tubing string, DaicelChiralCel OD (10 μm) tubing string, Daicel ChiralPak IA (5 μm) tubing string, Daicel ChiralPakIB (5 μm) tubing string, Daicel ChiralPak IC (5 μm) tubing string or (R, R)-Whelk-01 (5 μm).The representative condition of chirality HPLC is that (EtOH, at such as NEt for eluent A 3and/or the alkali of diethylamine or as under the sour presence or absence of TFA) with eluent B (hexane) etc. degree mixture, flow velocity is 8 to 34mL/min.
Embodiment
Experimental section:
Abbreviation (as used herein):
AcOEt ethyl acetate
AcOH acetic acid
Aq. the aqueous solution
Bdg combines
BSA bovine serum albumin
Bu normal-butyl
Ca. about (Latin: circa)
Cbz carbobenzoxy-(Cbz)
CC column chromatography on silica gel
CDI carbonyl dimidazoles
Comb. through merging
Conc. dense
DBU 1,8-diazabicylo [5.4.0] 11-7-alkene
DCC 1,3-dicyclohexyl carbodiimide
DCM methylene dichloride
DIPEA DIPEA
DMAP N, N-dimethyl-4-aminopyridine
DME 1,2-glycol dimethyl ether
DMF dimethyl formamide
DMSO methyl-sulphoxide
The decay of dpm per minute
EDTA ethylenediamine tetraacetic acid (EDTA)
EDC 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide
Ee enantiomerism is excessive
Eq. equivalent
EtOH ethanol
ESI-MS electrospray ionization mass spectrometry is analyzed
Chloro-N, N, the 2-trimethylammonium of Grignard reagent 1--1-allylamine
(Ghosez's reagent)
H hour
HATU O-(7-azepine-1H-benzotriazole-1-base)-1,1,3,3-tetramethyl-urea
Phosphofluoric acid ester
Hept heptane
HPLC high performance liquid chromatography
HSA human serum albumin
Hv high vacuum
IPr sec.-propyl
L litre
LAH lithium aluminum hydride
LC-MS liquid chromatography (LC)-mass spectroscopy
M volumetric molar concentration [mol L -1]
Me methyl
MeCN acetonitrile
MeI methyl iodide
MeOH methyl alcohol
Mesyl methane sulfonyl
Meth. method
Min minute
MS mass spectroscopy
MW molecular weight
The equivalent concentration of N solution
The bromo-succimide of NBS N-
NEt 3triethylamine
NMR nucleus magnetic resonance
Org. organic
PBS phosphate buffered normal saline solution
PG protecting group
PGD 2pGD 2
PMSF phenylmethanesulfonyl fluoride
Prep. preparative
R.t. room temperature
S second
Sat. saturated
Si-carbonic ether take polymkeric substance as the carbonic ether of carrier
Si-DEA take polymkeric substance as the diethylamine of carrier
Soln. solution
Subst. be substituted
TBTU O-(benzotriazole-1-base)-N, N, N ', N'-tetramethyl-urea Tetrafluoroboric acid
Ester
Tert. uncle
TFA trifluoroacetic acid
THF tetrahydrofuran (THF)
Tosyl p-toluenesulfonyl
T rresidence time
Tris tri-(methylol) aminomethane buffer solution
Chemical reaction
General remark
Unless otherwise noted, otherwise use as from commercial source obtain all solvents and reagent.
Temperature represents with degree Celsius (DEG C).Unless otherwise noted, otherwise reaction carry out under room temperature (r.t).
Unless otherwise instructed, otherwise in mixture, the relation of the solvent of liquid form or each several part of eluent or reagent mixture provides with volume relationship (v/v).
Analysis mode HPLC condition used in following instance:
LC-MS 1
LC-MS condition: analysis mode pump: Waters Acquity binary solvent manager, MS:WatersSQ detector, DAD:Acquity UPLC PDA detector, ELSD:Acquity UPLCELSD.Tubing string: Acquity UPLC BEH C181.7mm 2.1 × 50mm (ID), purchased from Waters, constant temperature in Acquity UPLC tubing string manager.Eluent: A:H 2o+0.05% formic acid or TFA; B:MeCN+0.05% formic acid or TFA.Method: gradient: through 2.00 minutes 2%B to 98%B.Flow velocity: 1.2mL/min.Detect: UV/Vis and/or ELSD and MS, t rin minute.
LC-MS 1FA: eluent: A:H 2o+0.05% formic acid; B:MeCN+0.05% formic acid.
LC-MS 1TFA: eluent: A:H 2o+0.05%TFA; B:MeCN+0.05%TFA.
LC-MS 2 to LC-MS 5
Through being equipped with Dionex Ultimate 3000RS photorectifier array detector, DionexUltimate 3000RS pump and Dionex MSQ +mass spectrometric Ultimate 3000RS Dionex HPLC instrument performs HPLC/MS and analyzes.
Following elution requirement is used to obtain the LC residence time:
-LC-MS 2: carry out analysis mode HPLC through Waters X-Bridge C18 tubing string (4.6mm × 30mm, 2.5 μm, Waters); The linear gradient of water/0.04%TFA (A) and MeCN (B) is through 1.5 minutes 5% to 95%B; Flow velocity is 4.5mL/min, detects under 215nm.
-LC-MS 3: warp sB-AQ tubing string (4.6mm × 50mm, 3.5 μm, Agilent) carries out analysis mode HPLC; The linear gradient of water/0.04%TFA (A) and MeCN (B) is through 1.5 minutes 5% to 95%B; Flow velocity is 4.5ml/min, detects under 215nm.
-LC-MS 4: carry out analysis mode HPLC through Waters Atlantis T3 tubing string (4.6mm × 30mm, 5 μm, Waters); The linear gradient of water/0.04%TFA (A) and MeCN (B) is through 1.5 minutes 5% to 95%B; Flow velocity is 4.5mL/min, detects under 215nm.
-LC-MS 5: carry out analysis mode HPLC through Supelco Ascentis Express C18 tubing string (5mm × 2.1mm, 2.7 μm, Supelco); The linear gradient of water/0.05% formic acid (A) and MeCN (B) is through 2.5 minutes 5% to 95%B; Flow velocity is 1.8mL/min, detects under 214nm and 254nm.
Through being equipped with the Gilson HPLC system of Gilson 215 self-actuated sampler, Gilson 333/334 pump, Finnigan AQA MS detector system and Dionex UV detector, use Waters XbridgeC18 or Waters Atlantis tubing string, perform preparation HPLC/MS purifying with the linear gradient of water/formic acid 0.02% (A) and MeCN (B) (acidic conditions) or water/ammoniacal liquor 0.02% (A) and MeCN (B) (alkaline condition).
Through Varian Mercury 300VX FT-NMR spectrograph or through Bruker Advance II 400 spectrograph record 1h-NMR spectrum.Unless otherwise indicated, otherwise all spectrum all at room temperature record.Chemical shift (δ) is reported with the PPM (ppm) of the proton resonance produced relative to the incomplete deuterate by NMR solvent, such as DMSO, δ (H) is 2.49ppm, and abbreviation s, d, t, q, m and br refer to unimodal, doublet, triplet, quartet, multiplet and broad peak respectively.Coupling constant J is in Hz.
Synthesis type (I) compound:
Following instance illustrates the preparation of the compounds of this invention, but does not limit category of the present invention.First, describe the synthesis of the Compound of Example of formula (I), describe the synthesis of intermediate and initial substance afterwards.When for experimental section, universal architecture 1,2,3 etc. refers to the respective structure described in previous general remark of preparation formula (I) compound.
The general method of preparation formula (I) compound:
Saponification reaction
The 1MNaOH aqueous solution (0.13mL) is added in solution in THF (0.5mL) of the ester (0.10mmol, 1 equivalent) of structure 1.At room temperature stir gained solution 14 hours.Vacuum removes organic solvent.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM (3 × 5mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purification of crude product and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to the compound of method corresponding construction 1 mentioned above is enumerated in following table 1.
Table 1
Alkylation of phenol and saponification reaction subsequently
To phenol 13 (0.20mmol, 1.0 equivalents) and K 2cO 3ethyl bromoacetate (33 μ L, 0.30mmol, 1.5 equivalents) is added in (83mg, 0.60mmol, 3.0 equivalents) solution in DMF (1mL).At room temperature stirred reaction mixture 5 hours.Add the 1M NaOH aqueous solution (0.5mL).At room temperature stir the mixture 89 hours.With the careful neutralization solution of formic acid (0.5mL), filter and by preparation HPLC (tubing string: Waters X-bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to method corresponding phenol 13 mentioned above is enumerated in following table 2.
Table 2
Acid amides coupling and saponification reaction subsequently
Method A: to 2-(1,2-benzoisoxazole-3-base) acetic acid (20mg, 0.10mmol, 1.0 equivalents) add TBTU (32mg in solution in DMF (0.5mL), 0.10mmol, 1.0 equivalents) and Si-DEA (400mg, 0.50mmol, 5.0 equivalents).At room temperature stir gained mixture 5 minutes.Add (±)-[the fluoro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (44mg, 0.12mmol, the 1.2 equivalents) solution in DCM (1mL).At room temperature stir the mixture 18 hours.Filter gained suspension, rinse solid with DCM (5mL), and vacuum concentrated filtrate.Resistates to be dissolved in THF (1mL) and to add the 0.2M NaOH aqueous solution (1mL).At room temperature stir gained mixture 30 minutes.With 0.2M HCl aqueous solution neutralise mixt and vacuum concentration.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 3.
Table 3
Method B: sequentially add DIPEA (34 μ L in the solution of 2-methylhydrocinnamic acid (12mg, 0.08mmol, 1.5 equivalents) in DMF (1mL), 0.20mmol, 4.0 equivalents) and TBTU (24mg, 0.08mmol, 1.5 equivalents).At room temperature stir gained solution 30 minutes.Then add (±)-[the chloro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (17mg, 0.05mmol, 1.0 equivalents) and at room temperature stir gained mixture 18 hours.Add the 1M NaOH aqueous solution (0.50mL).At room temperature stir the mixture 2 hours.With formic acid (0.50mL) neutralization solution, filter then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 4.
Table 4
Method C: to 3-phenylpropionic acid (23mg, 0.16mmol, 1.1 equivalents) in DMF/THF (4:1, HATU (108mg, 0.28mmol, 2.0 equivalents) and DIPEA (49 μ L is added in solution 1mL), 0.28mmol, 2.0 equivalents).At room temperature stir gained mixture 30 minutes.(±)-[fluoro-2-(1 of 4-is added at 0 DEG C, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (51mg, 0.14mmol, 1.0 equivalents) and DIPEA (49 μ L, 0.28mmol, 2.0 equivalents) solution in DCM/THF (4:1,1mL).At room temperature stir the mixture 18 hours.Saturated NaHCO is used with DCM diluted reaction mixture 3the aqueous solution and water washing.Vacuum concentration organic phase.Resistates to be dissolved in THF (2mL) and to add the 1M NaOH aqueous solution (2mL).At room temperature stir the mixture 5 hours.With acetic acid (pH<5) acidifying mixture.Add water (2mL) and DCM (2mL).Be separated each layer and vacuum concentration organic phase.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 5.
Table 5
Method D: to (±)-[fluoro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (37mg, 0.10mmol, 1.0 equivalents) add Si-carbonic ether (220mg) in suspension in DCM (1mL).At room temperature stir the mixture 1 hour, filter, and vacuum concentrated filtrate, obtain unhindered amina.
The solution of Grignard reagent in DCM (0.21mmol, 2.1 equivalents) is added in the solution of 2-naphthylacetic acid (28mg, 0.15mmol, 1.5 equivalents) in DCM (1mL).At room temperature stir gained mixture 10 minutes.Add unhindered amina and Si-DEA (0.45mmol, the 4.5 equivalents) solution in DCM (0.5mL).At room temperature stir the mixture 1 hour, filter and vacuum concentration.Resistates to be dissolved in THF (0.5mL) and to add the 0.2M NaOH aqueous solution.At room temperature stir the mixture 20 minutes, then with the neutralization of the 1M HCl aqueous solution, and vacuum concentration.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 6.
Table 6
Method E: to (±)-[fluoro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (42mg, 0.10mmol, 1.0 equivalents) and [(2-chlorobenzyl) oxygen base] acetic acid (20mg, 0.10mmol, 1.0 equivalents) sequentially add N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (29mg in solution in DMF (1.2mL), 0.15mmol, 1.5 equivalents) and 4-(dimethylamino) pyridine (31mg, 0.25mmol, 2.5 equivalents).At room temperature stir the mixture 86 hours.With AcOEt (10ml) dilution mixture thing.With the 1M HCl aqueous solution (2 × 5mL), saturated NaHCO 3the aqueous solution (2 × 5mL), the saturated NaCl aqueous solution (1 × 5mL) wash dilute solution, through MgSO 4dry and vacuum concentration.Resistates is dissolved in THF (0.5mL).Add the 1M NaOH aqueous solution (0.28mL).At room temperature stir the mixture 17 hours.Vacuum concentrated mixture.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM/THF 2:1 (3 × 6mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters X-Bridge, 19mm × 50mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 7.
Table 7
Carbamate formation and saponification reaction subsequently
Method A: to (±)-[the fluoro-2-of 4-(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of 6-)-phenoxy group]-ethyl acetate (5mg, 0.014mmol, 1.0 equivalents) and NEt 3chloroformic acid benzyl ester (2 μ L, 0.016mmol, 1.1 equivalents) is added in (4 μ L, 0.028mmol, 2.0 equivalents) solution in DCM (1mL).At room temperature stir gained solution 18 hours.Evaporating solvent and resistates being dissolved in DMF (0.5mL).Add the 1MNaOH aqueous solution (0.50mL).At room temperature stir the mixture 2 hours.With formic acid (0.50mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 18mm × 50mm, 10 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the corresponding chloro-formic ester of method corresponding construction 2 mentioned above is enumerated in following table 8.
Table 8
Method B: add ethanol (0.25mmol, 1.10 equivalents) and NEt under-10 DEG C (acetone/ice bath) in the solution of 15 points of clockwise triphosgene (22mg, 0.07mmol, 0.33 equivalent) in MeCN (0.15mL) 3(41 μ L, 0.31mmol, 1.4 equivalents) solution in MeCN (0.8mL).Stir the mixture at-10 DEG C 30 minutes again, then slowly add (±)-[fluoro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (77mg, 0.22mmol, 1.00 equivalents) and NEt 3(87 μ L, 0.62mmol, 2.8 equivalents) solution in MeCN (0.46mL).Make reaction mixture slowly be warming up to room temperature (30 minutes ice baths, then room temperatures), and at room temperature stir 18 hours.Use AcOEt diluted reaction mixture, with water and saturated NaCl solution washing, through MgSO 4drying, filters and evaporation.The 1M NaOH aqueous solution (0.5mL) is added in the solution of resistates in DMF (0.5mL).At room temperature stirred solution 18 hours.With formic acid neutralization reaction mixture, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 5 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the correspondent alcohol of method corresponding construction 2 mentioned above is enumerated in following table 9.
Table 9
Example 180:(±)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C27H26NO5Cl, MW=479.96)
By trifluoroacetic acid (0.92mL, 11.8mmol, 20.0 equivalents) be added into (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (280mg, 0.59mmol, 1.0 equivalents) in solution in DCM (1mL).At room temperature stir gained mixture 5 hours.Vacuum concentrated mixture.Chloroformic acid benzyl ester (0.18mL, 1.18mmol, 2.0 equivalents) is dropwise added in ice-cold suspension in DCM (1mL) to resistates and triethylamine (0.41mL, 2.95mmol, 5.0 equivalents).When the addition is complete, cooling bath is removed and at room temperature stirred suspension 18 hours.React with 1M aqueous citric acid solution (5mL) cancellation.Be separated each layer.By DCM (3 × 2mL) aqueous phase extracted.Through MgSO 4dry organic phase through merging and vacuum concentration.Resistates is dissolved in DMF (1mL), adds the 1M NaOH aqueous solution (1mL).At room temperature stir gained solution 18 hours.With formic acid (1mL) neutralization solution, filter then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
LC-MS 1FA：t R=0.98min；[M+H] +=480.1。
The sulfonylation that copper mediates and saponification reaction subsequently
The bromo-1-of (±)-7-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3 is stirred at 100 DEG C, 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (54mg, 0.10mmol, 1.0 equivalents),-sulfinic acid sodium (0.10mmol, 1.0 equivalents), L-PROLINE (2.3mg, 0.02mmol, 0.2 equivalent), 1M NaOH (20 μ L, 0.02mmol, 0.2 equivalent) and cupric iodide (I) (1.9mg, 0.01mmol, 0.1 equivalent) mixture in DMSO (1mL) 48 hours.Make mixture be cooled to room temperature and be allocated in AcOEt (15mL) and H 2between O (15mL).Be separated each layer and by AcOEt (2 × 15mL) aqueous phase extracted.Through MgSO 4dry organic phase through merging and vacuum concentration.Resistates is dissolved in THF (0.5mL), adds the 1M NaOH aqueous solution (0.28mL) and at room temperature stir the mixture 14 hours.Vacuum removes organic solvent.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM (3 × 5mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters Atlantis, 19mm × 50mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white solid.
To enumerate according to the method mentioned above bromo-1-of (±)-7-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3 in following table 10,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate, the bromo-1-of (±)-5-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3, the example of formula (I) compound that 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate or (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates and corresponding-sulfinic acid sodium are prepared as initial substance.
Table 10
Suzuki cross coupling and saponification reaction subsequently
At N 2lower to (±)-1-(the bromo-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (52mg, 0.10mmol, 1.00 equivalents), boric acid (0.10mmol, 1.0 equivalents) and sodium carbonate (42mg, 0.40mmol, 4.00 equivalents) add wantonly (triphenylphosphine) palladium (0) (6mg in mixture in toluene/EtOH/ water 20:4:1 (2.5mL), 0.005mmol, 0.05 equivalent).Stir the mixture at 100 DEG C 24 hours.Mixture is made to be cooled to room temperature and vacuum concentration.Resistates is allocated between AcOEt (10mL) and water (10mL).Be separated each layer.Organic phase is washed, through MgSO with the saturated NaCl aqueous solution (1 × 5mL) 4dry and via diatomite filtration.Vacuum concentrated filtrate.Resistates is dissolved in THF (0.5mL).Add the 1M NaOH aqueous solution (0.28mL) and at room temperature stir the mixture 14 hours.Vacuum removes organic solvent.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM (3 × 5mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters Atlantis, 19mm × 50mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance with corresponding boric acid according to method mentioned above is enumerated in following table 11.
Table 11
Alcohol alkylation and saponification reaction subsequently
Method A: add sodium hydride (25mg, 0.62mmol, 7.0 equivalents) in the ice cold solution of ethanol (0.42mmol, 5.0 equivalents) in DMF (0.6mL).Stir the mixture at 0 DEG C 1 hour.Add (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1; 2; 3; 4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate (40mg; 0.09mmol, 1.0 equivalents) solution in DMF (0.6mL) and at room temperature stirred reaction mixture 18 hours.Add water (20 μ L) and at room temperature stir the mixture again 1 hour.Vacuum concentration reaction mixture.Resistates is dissolved in THF (0.7mL).Add the 1M NaOH aqueous solution (0.3mL).At room temperature stirred solution 18 hours.With the 1M HCl aqueous solution (0.5mL) acidified reaction mixture and vacuum concentration.Resistates to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
The example of formula (I) compound prepared as initial substance according to method correspondent alcohol mentioned above is enumerated in following table 12.
Table 12
Method B: to (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1; 2; 3; 4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate (50mg; 0.11mmol, 1.0 equivalents) and the solution of ethanol (0.13mmol, 1.2 equivalents) in toluene (1mL) in add the 30%NaOH aqueous solution (1mL) and hydrogen sulfate TBuA (7.3mg; 0.02mmol, 0.2 equivalent).At room temperature after violent stirring 18 hours, with water (2mL) diluted reaction mixture, with 1M HCl acidified aqueous solution and with DCM extraction (3 times).Through MgSO 4the dry organic layer through merging, filters and vacuum concentration.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
The example of formula (I) compound prepared as initial substance according to method correspondent alcohol mentioned above is enumerated in following table 13.
Table 13
Urea synthesis and saponification reaction subsequently
Method A: isocyanic ester (0.22mmol, 1.1 equivalents) is dropwise added into (±)-[fluoro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (73mg, 0.20mmol, 1.0 equivalents) and NEt 3in (0.09mL, 0.62mmol, 3.1 equivalents) ice cold solution in DCM (5.5mL).At room temperature stir gained reaction mixture 60 hours.Saturated NaHCO is used with DCM dilution mixture thing 3the aqueous solution and water washing.Through MgSO 4dry organic layer, filters and vacuum concentration.The 1M NaOH aqueous solution (0.25mL) is added in the solution of crude product in DMF (0.9mL).At room temperature stirred solution 18 hours.With the 1M HCl aqueous solution (0.25mL) souring soln, filter and by preparation HPLC (tubing string: Waters X-bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the corresponding isocyanic ester of method corresponding construction 2 mentioned above is enumerated in following table 14.
Table 14
-(2-{2-[2-(2-chloro-base)-ethyl carbamyl]-1 method B: example 204:(±); 2; 3,4-tetrahydro-isoquinoline-1-base } the fluoro-phenoxy group of-4-)-acetic acid (C26H24N2O4ClF, MW=482.94)
Through 15 points of clockwise triphosgene (20mg under-10 DEG C (acetone/ice bath), 0.07mmol, 0.33 equivalent) add 2-(2-chloro-phenyl-) ethamine (33 μ L in solution in MeCN (0.3mL), 0.22mmol, 1.10 equivalents) and triethylamine (39 μ L, 0.28mmol, 1.30 equivalents) solution in MeCN (2mL).Stir the mixture again at 0 DEG C 30 minutes, then slowly (±)-[fluoro-2-(1 of 4-is added, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (73mg, 0.20mmol, 1.00 equivalents) and triethylamine (78 μ L, 0.56mmol, 2.80 equivalents) solution in MeCN (1mL).Make reaction mixture slowly be warming up to room temperature (30 minutes ice baths, then room temperatures), and at room temperature stir 60 hours.Use AcOEt diluted reaction mixture, with water and saturated NaCl solution washing, through MgSO 4drying, filters and evaporation.The 1M NaOH aqueous solution (0.25mL) is added in the solution of crude product in DMF (0.9mL).At room temperature stirred solution 18 hours.With the 1M HCl aqueous solution (0.25mL) souring soln, then by preparation HPLC (tubing string: Waters X-bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain title compound.
LC-MS 1FA：t R=0.84min；[M+H] +=483.1。
Sulphonamide formation and saponification reaction subsequently
By SULPHURYL CHLORIDE (0.18mmol; 1.0 equivalents) and DIPEA (0.33mL; 1.92mmol; 10.6 equivalents) be added into (±)-{ 2-[2-(2-Amino-acetyl)-1; 2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate hydrochloride (81mg; 0.18mmol, 1.0 equivalents) in solution in DCM (3mL).At room temperature stir the mixture 2 hours.By 1M KH 2pO 4the aqueous solution (3mL) is added in mixture.Be separated each layer and with DCM aqueous phase extracted (twice).The organic phase of vacuum concentration through merging.Resistates to be dissolved in THF (0.8mL) and to add the 1M NaOH aqueous solution (0.4mL).At room temperature stirred solution 18 hours.With water (2mL) and the 1M HCl aqueous solution (0.4mL), use DCM diluting soln afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
The example of formula (I) compound prepared as initial substance by corresponding SULPHURYL CHLORIDE according to method mentioned above is enumerated in following table 15.
Table 15
Sulphonamide formation, alkylation and saponification reaction subsequently
By SULPHURYL CHLORIDE (0.18mmol; 1.0 equivalents) and DIPEA (0.33mL; 1.92mmol; 10.6 equivalents) be added into (±)-{ 2-[2-(2-Amino-acetyl)-1; 2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate hydrochloride (81mg; 0.18mmol, 1.0 equivalents) in solution in DCM (3mL).At room temperature stir the mixture 2 hours.By 1M KH 2pO 4the aqueous solution (3mL) is added in mixture.Be separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Sodium hydride (9mg, 0.22mmol, 1.2 equivalents) is added in the ice cold solution of resistates in DMF (1mL).At room temperature stirred reaction mixture 30 minutes.Add methyl iodide (23 μ l, 0.36mmol, 2.0 equivalents) and at room temperature stir gained mixture 18 hours.By mixture impouring H 2in O and with DCM extraction (3 times).The organic phase of vacuum concentration through merging.Resistates to be dissolved in DMF (0.8mL) and to add the 1MNaOH aqueous solution (0.4mL).At room temperature stirred solution 18 hours.With water (2mL) and the 1M HCl aqueous solution (0.4mL), use DCM diluting soln afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
The example of formula (I) compound prepared as initial substance by corresponding SULPHURYL CHLORIDE according to method mentioned above is enumerated in following table 16.
Table 16
Example 213:(±)-1-(5-carbamyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H24N2O6, MW=460.49)
At room temperature to (±)-1-(5-cyano group-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (141mg, 0.30mmol, 1.0 equivalents) add hydrogen (dimethyl phosphonous acid-kP) [hydrogen two (dimethyl phosphonous acid ester group-kP)] platinum (II) (26mg with whole part in solution in EtOH (0.5mL) and water (0.12mL), 0.06mmol, 0.2 equivalent).At 70 DEG C, stirred reaction mixture 1 hour, is then cooled to room temperature.Then via at SiO 2containing Na on layer 2sO 4the short string filtration product solution of layer (each layer depth 1cm), with AcOEt (200mL) wash-out.Vacuum concentrated filtrate.The 1M NaOH aqueous solution (0.5mL) is added in the solution of resistates in DMF (2mL).At room temperature stir gained solution 6 hours.With formic acid (0.5mL) neutralise mixt, filter and by preparation HPLC (tubing string: Waters X-bridge, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
LC-MS 1FA：t R=0.67min；[M+H] +=461.2。
Example 214:(±)-1-[2-Carboxvmethoxv-5-(5-sulfo--4,5-dihydro-[1,2,4] oxadiazole-3-bases)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C27H23N3O6S, MW=517.56)
Hydroxylamine hydrochloride (139mg, 2.00mmol, 10.0 equivalents) and NaHCO is stirred at 50 DEG C 3(202mg, 2.40mmol, 12.0 equivalents) mixture in DMSO (1mL) 1 hour.Add (±)-1-(5-cyano group-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (94mg, 0.20mmol, 1.0 equivalents) and at 80 DEG C, stir gained new blend 1 hour.Water is added in reaction mixture, adds AcOEt afterwards.Be separated each layer and by saturated NaCl solution washing organic phase, through MgSO 4drying, filters and vacuum concentration.Resistates is dissolved in THF (1mL).Add 1,1'-thiocarbonyldiimidazole (39mg, 0.21mmol, 1.05 equivalents) and DBU (21 μ L, 0.14mmol, 0.7 equivalent), and at room temperature stir the mixture 3 hours.Add water and extract mixture with AcOEt.Be separated each layer and in succession use saturated NaHCO 3the aqueous solution and saturated NaCl solution washing organic phase, then through MgSO 4drying, filters and vacuum concentration.The 1M NaOH aqueous solution (0.25mL) is added in the solution of resistates in THF (0.9mL).At room temperature stirred solution 18 hours.
With water (2mL) and the 1M HCl aqueous solution (0.25mL), use DCM diluting soln afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.LC-MS 1FA：t R=0.79min；[M+H] +=518.1。
Example 215:(±)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-4-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H22NO5F, MW=435.45)
At N 2under at room temperature stir (±)-1-(the fluoro-phenyl of 2-allyloxy-4-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (200mg, 0.48mmol, 1.00 equivalents), 1,3-dimethyl barbituric acid (150mg, 0.96mmol, 2.00 equivalents) and wantonly (triphenylphosphine) palladium (0) (28mg, 0.02mmol, 0.05 equivalent) mixture in MeOH (5mL) 5 hours.Mixture is allocated between AcOEt (25ml) and water (25ml).Be separated each layer and by AcOEt (2 × 25mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration.To resistates and Cs 2cO 3ethyl bromoacetate (79 μ L, 0.72mmol, 1.50 equivalents) is added in (468mg, 1.44mmol, 3.00 equivalents) solution in DMF (3mL).Stirred reaction mixture 5 hours at 50 DEG C.With water (25mL) and AcOEt (50mL) diluted reaction mixture.Be separated each layer.By AcOEt (2 × 25mL) aqueous phase extracted.By water (1 × 25mL), the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration.The 1M NaOH aqueous solution (2mL) is added in the solution of resistates in DMF (2mL).Gained solution is stirred 5 hours at 50 DEG C.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
LC-MS 1FA：t R=0.87min；[M+H] +=436.1。
Example 216:(±)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-6-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H22NO5F, MW=435.45)
At N 2under at 50 DEG C, stir (±)-1-(the fluoro-phenyl of 2-allyloxy-6-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (60mg, 0.14mmol, 1.00 equivalents), 1,3-dimethyl barbituric acid (45mg, 0.29mmol, 2.00 equivalents) and wantonly (triphenylphosphine) palladium (0) (8mg, 7 μm of ol, 0.05 equivalent) mixture in MeOH (5mL) 5 hours.Mixture is allocated between AcOEt (25ml) and water (25ml).Be separated each layer and by AcOEt (2 × 25mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration.To resistates and Cs 2cO 3ethyl bromoacetate (24 μ L, 0.22mmol, 1.50 equivalents) is added in (140mg, 0.43mmol, 3.00 equivalents) solution in DMF (2mL).Stirred reaction mixture 5 hours at 50 DEG C.With water (25mL) and AcOEt (50mL) diluted reaction mixture.Be separated each layer.By AcOEt (2 × 25mL) aqueous phase extracted.By water (1 × 25mL), the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration.The 1M NaOH aqueous solution (2mL) is added in the solution of resistates in DMF (2mL).Gained solution is stirred 5 hours at 50 DEG C.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
LC-MS 1FA：t R=0.86min；[M+H] +=436.2。
Example 217:(±)-1-[2-(3-carboxyl-propoxy-) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (27H26NO5F, MW=463.50)
By 4-bromobutyrate (45 μ L, 0.30mmol, 1.50 equivalents) be added into (±)-1-(the fluoro-2-hydroxy-pheny of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (75mg, 0.20mmol, 1.00 equivalents) and K 2cO 3in (83mg, 0.60mmol) solution in DMF (0.7mL).At room temperature stir the mixture 2 hours.Add 4-bromobutyrate (22 μ l, 0.15mmol, 0.75 equivalent) again and at room temperature stir the mixture 18 hours.With AcOEt and water diluted reaction mixture.Be separated each layer and with AcOEt aqueous phase extracted (2 times).The organic phase through merging with water and saturated NaCl solution washing, through MgSO 4drying, filters and vacuum concentration.The 1M NaOH aqueous solution (0.50mL) is added in the solution of thick ester in THF (0.9mL).At room temperature stir gained solution 62 hours.Vacuum removes organic solvent.With water and the 1MHCl aqueous solution (0.8mL), dilute resistates with DCM afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).Through MgSO 4the dry organic phase through merging, filters and vacuum concentration.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying and evaporation (genevac), to obtain required acid.
LC-MS 1FA：t R=0.89min；[M+H] +=464.2。
Example 218:(±)-{ 4-cyano group-2-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid (C28H24N2O4, MW=452.51)
To (±)-1-(5-cyano group-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (188mg, 0.40mmol, 1.0 equivalents) dropwise add 2-bromo-1 in solution in DCM (1mL), 3,2-benzo dioxaborolan alkene (159mg, 0.80mmol, the 2.0 equivalents) solution in DCM (2mL).At room temperature stir the mixture 2 hours.Add water (2mL).At room temperature stir the mixture 20 minutes, then use DCM (30mL) to dilute.With the 10%NaOH aqueous solution (2 × 15mL), with the saturated NaCl aqueous solution (1 × 15mL) purging compound, and through MgSO 4dry.With the organic layer that 4M HCl dioxane solution (4mL) process is dry, at room temperature stir 1 hour, and vacuum concentration.Filter with heptane wet-milling resistates, obtain the hydrochloride in white solid.To gained salt and trans-2-cyclo-propane-1-formic acid (65mg, 0.40mmol, 1.0 equivalents) sequentially add N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (115mg in mixture in DMF (2mL), 0.60mmol, 1.5 equivalents) and 4-(dimethylamino) pyridine (147mg, 1.20mmol, 3.0 equivalents).At room temperature stir the mixture 20 hours.With AcOEt (15ml) dilution mixture thing.With the 1M HCl aqueous solution (2 × 5mL), saturated NaHCO 3the aqueous solution (2 × 5mL), the saturated NaCl aqueous solution (1 × 5mL) wash diluted solution, through MgSO 4dry and vacuum concentration.Resistates is dissolved in THF (1mL).Add the 1M NaOH aqueous solution (0.56mL).At room temperature stir the mixture 18 hours.Vacuum concentrated mixture.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM/THF 2:1 (3 × 6mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters X-Bridge, 19mm × 50mm, 10 μm, UV/MS, acidic conditions) Purification, obtain the required acid in white foam.
LC-MS 1FA：t R=0.79min；[M+H] +=453.2。
Example 219:(±)-1-(2-Carboxvmethoxv-5-cvano-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H22N2O5, MW=442.47)
By (±)-1-(the bromo-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (105mg, 0.20mmol, 1.0 equivalents) solution in DMF (10mL) adds zinc cyanide (23mg, 0.20mmol, 1.0 equivalents) and four (triphenylphosphine) palladiums (0) (23mg, 0.02mmol, 0.1 equivalent).Gained suspension is stirred 18 hours at 110 DEG C.After cooling, add Et 2o (100mL) and with the saturated NaCl aqueous solution (2 × 120mL) washing soln.Through MgSO 4dry organic layer, filters and vacuum removes solvent.The 1M NaOH aqueous solution (0.25mL) is added in the solution of crude product in DMF (0.9mL).At room temperature stirred solution 18 hours.With the 1M HCl aqueous solution (0.25mL) souring soln, then by preparation HPLC (tubing string: Waters X-bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain required acid.
LC-MS 1FA：t R=0.81min；[M+H] +=443.1。
Example 220:1-[2-((R)-1-carboxyl-oxyethyl group) the chloro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H24NO5Cl, MW=465.93)
To (±)-1-(5-chlorine-2-hydroxyl-phenyl)-3; 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (192mg; 0.30mmol; 1.0 equivalents) add (S)-2-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate (80mg in solution in MeCN (1mL); 0.30mmol; 1.0 equivalents) and Anhydrous potassium carbonate (83mg; 0.60mmol; 2.0 equivalents), and heated mixt to 65 DEG C maintains 18 hours.Add (S)-2-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate (40mg, 0.15mmol, 0.5 equivalent) again and at 90 DEG C heated mixt 4 hours.Make mixture be cooled to room temperature, and use Et 2o extracts (2 times), through MgSO 4drying, filters and vacuum concentration.The 1M NaOH aqueous solution (0.38mL) is added in the solution of thick ester in THF (1.3mL).At room temperature stirred solution 18 hours.With water (2mL) and the 1M HCl aqueous solution (0.38mL), use DCM diluting soln afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Crude mixture to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
LC-MS 1FA：t R=0.93min；[M+H] +=466.1。
Example 221:(S)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H22NO5F, MW=435.45)
By chiral preparative HPLC (tubing string: ChiralPak AD-H, 20mm × 250mm, 5 μm, UV, eluent: Hept/EtOH+0.1%TFA is 70/30) be separated (±)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate, produces 30.5mg (R)-enantiomer and 26.1mg (S)-enantiomer.Owing to there is EtOH in eluent mixture, therefore by acid moieties esterification.The 1M NaOH aqueous solution (0.18mL) is added in the solution of (S)-enantiomer in THF (0.6mL).At room temperature stirred solution 2 hours.Vacuum removes organic solvent.With water and the 1M HCl aqueous solution (0.18mL), dilute resistates with DCM afterwards.Concussion mixture, is then separated each layer and with DCM aqueous phase extracted (2 times).The organic phase of vacuum concentration through merging.Resistates to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Waers X-Bridge, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
LC-MS 1FA：t R=0.87min；[M+H] +=436.1。
Example 222:(±)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H25N2O7FS, MW=528.56)
At 150 DEG C, the bromo-1-of (±)-5-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3 is stirred under Ar, 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (108mg, 0.20mmol, 1.00 equivalents), amsacrine (23mg, 0.24mmol, 1.20 equivalents), N, N-N-methylsarcosine (4.3mg, 0.04mmol, 0.2 equivalent), Tripotassium phosphate (106mg, 0.50mmol, 2.5 equivalents) and cupric iodide (I) (7.6mg, 0.04mmol, 0.2 equivalent) mixture in DMF (2mL) 48 hours.Make mixture be cooled to room temperature and be allocated in AcOEt (25mL) and H 2between O (25mL).Be separated each layer and by AcOEt (2 × 25mL) aqueous phase extracted.Through MgSO 4dry organic phase through merging and vacuum concentration.Resistates to be dissolved in DMF (1.0mL) and to add the 1M NaOH aqueous solution (1.0mL).At room temperature stir the mixture 18 hours.With the 1M HCl aqueous solution (1.0mL) neutralization solution, then by preparation HPLC, (tubing string: Atlantis, 30mm × 75mm, 10 μMs, acidic conditions, detects: UV/MS) purifying, obtains required acid.
LC-MS 1FA：t R=0.72min；[M+H] +=529.1。
Example 223:(±)-1-(2-Carboxvmethoxv-5-[1,2,3] triazol-1-yl-phenyl)-3,4---dihydro-1H-isoquinoline 99.9-2-benzyl formate (C27H24N4O5, MW=484.51) and
Example 224:(±)-1-(2-Carboxvmethoxv-5-[1,2,3] triazole-2-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (27H24N4O5, MW=484.51)
At room temperature by 1H-1, 2, 3-triazole (23 μ L, 0.400mmol, 2.00 equivalent), cupric iodide (I) (1.9mg, 0.010mmol, 0.05 equivalent), cesium carbonate (130mg, 0.400mmol, 2.00 equivalents) and N, N'-Dimethyl-cyclohexane-1, 2-diamines (7 μ L, 0.040mmol, 0.20 equivalent) add as (±)-1-(the bromo-2-ethoxycarbonylmethoxy-phenyl of 5-)-3 in microwave tube, 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (105mg, 0.200mmol, 1.00 equivalents) in solution in DMF (0.1mL).Use N 2washpipe, seals and is heated to 120 DEG C of maintenances 60 hours.Dilute with water reaction mixture and washing with AcOEt.Remain aqueous phase with 1N HCl acidified aqueous solution and extract (3 times) with AcOEt.Through MgSO 4the dry organic extract through merging, filters and vacuum concentration.Thick resistates to be dissolved in again in DMF (1.2mL) and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, obtain (±)-1-(2-Carboxvmethoxv-5-[1,2,3] triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (LC-MS 1FA:t r=0.75min; [M+H] +=485.2) and (±)-1-(2-Carboxvmethoxv-5-[1,2,3] triazole-2-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (LC-MS 1FA:t r=0.85min; [M+H] +=485.1).
Example 225:(±)-{ the chloro-2-of 4-[2-(2-methyoxy-benzyl thiocarbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (C26H25N2O4ClS, MW=497.01)
To (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (76mg, 0.20mmol, 1.0 equivalents) and N-ethyl diisopropylamine (42 μ L, 0.24mmol, 1.2 equivalents) add isothiocyanic acid 2-methoxy benzyl ester (36mg, 0.20mmol, 1.0 equivalents) in solution in DCM (2mL).At room temperature stir gained mixture 19 hours.With DCM (20mL) dilution mixture thing, with the 10%AcOH aqueous solution (2 × 5mL) and with the washing of the saturated NaCl aqueous solution (1 × 5mL).Vacuum concentration organic layer.Resistates is dissolved in DMF (1mL).Add the 1M NaOH aqueous solution (0.5mL).At room temperature stir the mixture 7 hours.With the careful neutralization solution of formic acid (0.5mL), filter and by preparation HPLC (tubing string: Waters X-bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying, obtain the required acid in white solid.
LC-MS 1FA：t R=0.89min；[M+H] +=497.1。
Example 226:(±) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H21NO5ClF, MW=469.90) of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-
At N 2under at room temperature stir (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-6-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (65mg, 0.14mmol, 1.00 equivalents), 1,3-dimethyl barbituric acid (45mg, 0.29mmol, 2.00 equivalents) and wantonly (triphenylphosphine) palladium (0) (8.3mg, 0.007mmol, 0.05 equivalent) mixture in MeOH (3mL) 3 hours.Mixture is allocated between AcOEt (15ml) and water (15ml).Be separated each layer and by AcOEt (2 × 15mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 15mL) washing through merging, through MgSO 4drying, filters and vacuum concentration.Ethyl bromoacetate (48 μ L, 0.43mmol, 3.0 equivalents) is added in solution in DMF (2mL) to resistates and Anhydrous potassium carbonate (60mg, 0.43mmol, 3.0 equivalents).At room temperature stirred reaction mixture 2 hours.With water (15mL) and AcOEt (30mL) diluted reaction mixture.Be separated each layer.By AcOEt (2 × 15mL) aqueous phase extracted.By water (1 × 15mL), the organic phase of the saturated NaCl aqueous solution (1 × 15mL) washing through merging, through MgSO 4drying, filters and vacuum concentration.The 1M NaOH aqueous solution (0.6mL) is added in the solution of resistates in DMF (1.1mL).At room temperature stir gained solution 24 hours.With formic acid (0.6mL) souring soln.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purification of crude product and evaporation, obtain title compound.
LC-MS 3：t R=0.95min；[M+H] +=470.1。
Saponification reaction
The 1MNaOH aqueous solution (0.13mL) is added in solution in THF (0.5mL) of the ester (0.10mmol, 1 equivalent) of structure 1.At room temperature stir gained solution 14 hours.Vacuum removes organic solvent.Resistates is diluted and with 1M HCl acidified aqueous solution with water (2mL).Mixture is extracted with DCM (3 × 5mL).The organic phase of vacuum concentration through merging.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purification of crude product and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to the compound of method corresponding construction 1 mentioned above is enumerated in following table 17.
Table 17
Carbamate is formed and saponification reaction
Method A: to (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-nitro-phenyl (118mg, 0.20mmol, 1.0 equivalents) and 2, potassium tert.-butoxide (67mg is added in the solution of 4-3,5-dimethoxybenzoic alcohol (102mg, 0.60mmol, 3.0 equivalents) in THF (4.5mL), 0.60mmol, 3.0 equivalents).At room temperature stir the mixture 18 hours.Vacuum (genevac) removes solvent.Resistates is dissolved in MeCN/H 2in O (1mL, 1:1), add formic acid (0.2mL), add DMF (0.6mL) afterwards.By preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying gained solution, obtain required acid.
The example of formula (I) compound prepared as initial substance with corresponding 4-nitrophenols carbamate 7 and correspondent alcohol according to method mentioned above is enumerated in following table 18.
Table 18
Method B: to [the chloro-2-of 4-((S)-5,6-bis-fluoro-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (91mg, 0.21mmol, 1 equivalent) and DIPEA (90 μ L, 0.53mmol, 2.5 equivalents) add carbonic acid 2 in solution in DCM (3.3mL), the fluoro-benzyl ester of 5-dioxo-pvrrolidin-1-base ester 2-(70mg, 0.25mmol, 1.2 equivalents).At room temperature stir the mixture 1 hour.React with 1M aqueous citric acid solution (3.3mL) cancellation.Be separated each layer.By DCM (3 × 5mL) aqueous phase extracted.The concentrated organic phase through merging of vacuum (genevac).The 1MNaOH aqueous solution (0.55mL) is added in the solution of resistates in DMF (1mL).At room temperature stirred solution 1 hour.Add formic acid (0.1mL).By preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying gained acidic solution and evaporation (genevac), obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the corresponding carbonic ether 5 of method corresponding construction 2 mentioned above is enumerated in following table 19.
Table 19
Method C: to (±)-[the chloro-2-of 4-(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of 7-)-phenoxy group]-ethyl acetate hydrochloride (378mg, 0.94mmol, 1.0 equivalents) and NEt 3chloroformic acid benzyl ester (0.17mL, 1.13mmol, 1.2 equivalents) is added in (0.39mL, 2.83mmol, 3.0 equivalents) ice cold solution in DCM (10mL).Stirred solution 1 hour at 0 DEG C and more at room temperature stir 4 hours.With DCM (10mL) diluting reaction thing, and with 1M aqueous citric acid solution (20mL) cancellation.Be separated each layer.By DCM (3 × 10mL) aqueous phase extracted.Through Na 2sO 4dry organic phase through merging and vacuum concentration.The 1M NaOH aqueous solution (1.5mL) is added in the solution of resistates in DMF (3mL).At room temperature stir gained mixture 18 hours.With formic acid (about 1.5mL) neutralization reaction mixture, and by preparation HPLC (tubing string: Water X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
The example of formula (I) amine prepared as initial substance according to the amine of method corresponding construction 2 mentioned above is enumerated in following table 20.
Table 20
Michael addition and saponification reaction subsequently
By Potassium monofluoride 40 % by weight/aluminum oxide (216mg; 3.72mmol; 17.2 equivalents) be added into (±)-[2-(2-acryl-1; 2,3,4-tetrahydro-isoquinoline-1-base) the chloro-phenoxy group of-4-]-ethyl acetate (100mg; 0.22mmol; 1.0 equivalents) and the mixture of the fluoro-3-skatole of 5-(33mg, 0.22mmol, 1.0 equivalents) in MeCN (1mL) in.Gained suspension is stirred 18 hours at 80 DEG C.Add formic acid (0.2mL).Filter reaction mixture and by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying filtrate and vacuum concentration, obtain the required product in white foam.
The example of formula (I) compound prepared as initial substance according to method mentioned above corresponding ethernamine 8 and corresponding heterocycle 9 is enumerated in following table 21.
Table 21
Acid amides coupling and saponification reaction subsequently
Method A: to (2-methoxyphenoxy) acetic acid (22mg, 0.12mmol, 1.2 equivalents) add TBTU (39mg in solution in DMF (0.3mL), 0.12mmol, 1.2 equivalents) and Si-DEA (400mg, 0.50mmol, 5.0 equivalents).At room temperature stir gained mixture 30 minutes.Add (±)-[the chloro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (38mg, 0.10mmol, the 1.0 equivalents) solution in DCM/DMF 5:1 (0.6mL).At room temperature stir the mixture 18 hours.Filter gained suspension, rinse solid with DCM (5mL), and vacuum concentrated filtrate.Resistates to be dissolved in THF (mL) and to add the 1M NaOH aqueous solution (1mL).At room temperature stir gained mixture 30 minutes.With 2M HCl acidified aqueous solution mixture and vacuum concentration.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 22.
Table 22
Method B: to 3-(2,4-3,5-dimethylphenyl) propionic acid (18mg, 0.10mmol, 1.0 equivalents) and (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (41mg, 0.10mmol, 1.0 equivalents) add DMAP (49mg, 0.40mmol, 4.0 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (29mg in solution in DMF (1.2mL), 0.15mmol, 1.5 equivalents).At room temperature stir gained solution 18 hours.Add the 1M NaOH aqueous solution (0.6mL) and at room temperature stirred solution 2 hours.Add formic acid (0.2mL).By preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purification of crude mixture and evaporation (genevac), obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 23.
Table 23
Method C: to (±)-trans-2-ethyl-cyclopropyl alkane formic acid (35mg, 0.31mmol, 1.3 equivalents) sequentially add DIPEA (4 equivalent) and TBTU (98mg, 0.31mmol, 1.3 equivalents) in solution in DMF (2mL).At room temperature stir gained solution 30 minutes.Add (the chloro-2-1 of (S)-4-, 2,3,4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate hydrochloride (90mg, 0.24mmol, 1.0 equivalents) and at room temperature stir gained mixture 18 hours.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (genevac) concentrate.The 1M NaOH aqueous solution (0.5mL) is added in the solution of ethyl ester derivative in DMF (1mL).At room temperature stir the mixture 18 hours.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (Genevac) concentrate, obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 24.
Table 24
The chloro-2-of example 464:{4-[(S)-2-(trans-2-sec.-propyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group-acetic acid (diastereomer 1) (C24H26NO4Cl, MW=427.93) and
The chloro-2-of example 465:{4-[(S)-2-(trans-2-sec.-propyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (diastereomer 2) (C24H26NO4Cl, MW=427.93)
To (±)-trans-2-sec.-propyl-cyclopropane-carboxylic acid (39mg, 0.31mmol, 1.3 equivalents) sequentially add DIPEA (4 equivalent) and TBTU (98mg, 0.31mmol, 1.3 equivalents) in solution in DMF (2mL).At room temperature stir gained solution 30 minutes.Add (the chloro-2-1 of (S)-4-, 2,3,4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate hydrochloride (90mg, 0.24mmol, 1.0 equivalents) and at room temperature stir gained mixture 18 hours.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (genevac) concentrate.The 1M NaOH aqueous solution (0.5mL) is added in the solution of ethyl ester derivative in DMF (1mL).At room temperature stir the mixture 18 hours.With formic acid (1mL) neutralization solution, then by preparation HPLC (tubing string: Waters XBridge, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying and vacuum (genevac) concentrate, obtain { the chloro-2-of 4-[(S)-2-(trans-2-sec.-propyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (diastereomer 1) (LC-MS 1FA:t r=1.13min; [M+H] +=428.3) and { the chloro-2-of 4-[(S)-2-(trans-2-sec.-propyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid (diastereomer 2) (LC-MS 1FA:t r=1.15min; [M+H] +=428.3).
Example 466:(±)-{ the chloro-2-of 4-[2-(2,2-dimethyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (C23H24NO4Cl, MW=413.90)
To (±)-2,2-dimethyl-cyclopropane-carboxylic acid (26mg, 0.20mmol, 1.0 equivalents) and (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (73mg, 0.20mmol, 1.0 equivalents) add DMAP (37mg, 0.30mmol, 1.5 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (58mg in solution in DMF (2.4mL), 0.30mmol, 1.5 equivalents).At room temperature stir gained solution 62 hours.Add the 1M NaOH aqueous solution (1.2mL) and at room temperature stirred solution 3.5 hours.Add formic acid (0.2mL).Crude mixture is by preparation HPLC (tubing string: WatersXBridge, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying.Be separated two kinds of racemize diastereomer (LC-MS 3:t r(±)-diastereomer 1=0.91 and t r(±)-diastereomer 2=0.93).Title compound shows: t r=0.93.
LC-MS 1FA：t R=1.09min；[M+H] +=414.3。
Example 467:(±)-(the chloro-2-{2-of 4-[2-(2,4-dimethyl thiazol-5-base)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C26H25N2O4ClS, MW=497.01)
To (±)-trans-2-(2,4-dimethyl thiazol-5-base)-cyclopropane-carboxylic acid (42mg, 0.20mmol, 1.0 equivalents) and (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (73mg, 0.20mmol, 1.0 equivalents) add DMAP (37mg, 0.30mmol, 1.5 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (58mg in solution in DMF (2.4mL), 0.30mmol, 1.5 equivalents).At room temperature stir gained solution 62 hours.Add the 1M NaOH aqueous solution (1.2mL) and at room temperature stirred solution 3.5 hours.Add formic acid (0.2mL).Crude mixture is by preparation HPLC (tubing string: Waters XBridge, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying.Be separated two kinds of racemize diastereomer (LC-MS 3:t r(±)-diastereomer 1=0.81 and t r(±)-diastereomer 2=0.82).Title compound shows: t r=0.82.LC-MS 1FA：t R=0.99min；[M+H] +=497.3。
Alcohol alkylation and saponification reaction subsequently
Method A: to 3-hydroxyl-6-picoline (13mg at 75 DEG C; 0.12mmol; 1.2 equivalents) and salt of wormwood (22mg; 0.16mmol; 1.6 equivalents) add (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1 in mixture in MeCN (0.8mL); 2; 3; 4-tetrahydro-isoquinoline-1-base] the chloro-phenoxy group of-4-}-ethyl acetate (47mg; 0.10mmol, 1.0 equivalents) solution in MeCN (0.2mL).Stirred reaction mixture 2 hours at 75 DEG C and more at room temperature stir 18 hours.Add 1M NaOH water mixture (1mL) and at room temperature stir the mixture 1 hour.With 2M HCl acidified aqueous solution mixture, by preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to method correspondent alcohol mentioned above is enumerated in following table 25.
Table 25
Method B: add the mineral oil (4.4mg, 0.11mmol, 1.1 equivalents) containing 60% sodium hydride in the solution of 3-hydroxy-5-methyl yl pyridines (12mg, 0.10mmol, 1.0 equivalents) in DMF (1.0mL).At room temperature stir gained mixture 10 minutes.Add (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1; 2; 3; 4-tetrahydro-isoquinoline-1-base] the chloro-phenoxy group of-4-}-ethyl acetate (47mg; 0.10mmol, 1.0 equivalents) solution in DMF (0.3mL) and at room temperature stirred reaction mixture 4 hours.Add the 1M NaOH aqueous solution (1.0mL).At room temperature stirred solution 30 minutes.With the 2M HCl aqueous solution (1.0mL) acidified reaction mixture and vacuum concentration.Resistates to be dissolved in DMF (1.2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying, to obtain required acid.
The example of formula (I) compound prepared as initial substance according to method correspondent alcohol mentioned above is enumerated in following table 26.
Table 26
Alkylation and saponification reaction subsequently
To (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1; 2; 3; 4-tetrahydro-isoquinoline-1-base] the chloro-phenoxy group of-4-}-ethyl acetate (47mg, 0.10mmol, 1.0 equivalents) and cesium carbonate (65mg; 0.20mmol; 2.0 equivalents) add 3-skatole (13mg, 0.10mmol, 1.0 equivalents) in solution in DMF (0.8mL).Stir the mixture at 80 DEG C 17 hours.Make mixture be cooled to room temperature, add the 1M NaOH aqueous solution (0.2mL).At room temperature stir gained mixture 4 hours.With formic acid (about 0.2mL) neutralise mixt, and by preparation HPLC (tubing string: Water X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (Genevac) concentrate, obtain required acid.
The example of formula (I) compound prepared as initial substance with corresponding indoles according to method mentioned above is enumerated in following table 27.
Table 27
Urea formation and saponification reaction subsequently
To (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (50mg, 0.13mmol, 1.00 equivalents) and NEt3 (55 μ L, 0.39mmol, 3.00 equivalents) add MeCN (1mL) containing isocyanic acid 2-benzyl chloride ester (23mg, 0.14mmol, 1.05 equivalents) in solution in MeCN (1mL).At room temperature stir the mixture 18 hours.Add the 1M NaOH aqueous solution (0.5mL).At room temperature stir the mixture 18 hours.Use formic acid neutralization solution, and by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (Genevac) concentrate, obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the corresponding isocyanic ester of method corresponding construction 2 mentioned above is enumerated in following table 28.
Table 28
Suzuki cross coupling and saponification reaction subsequently
At N 2lower to the bromo-1-of (±)-7-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (113mg, 0.20mmol, 1.00 equivalents), 4-fluorobenzoic boric acid (29mg, 0.20mmol, 1.00 equivalents) and sodium carbonate (85mg, 0.80mmol, 4.00 equivalents) add wantonly (triphenylphosphine) palladium (0) (12mg in mixture in toluene/MeOH/ water 20:4:1 (4mL), 0.01mmol, 0.05 equivalent) and stir the mixture in sealed vial at 100 DEG C 18 hours.Mixture is made to be cooled to room temperature and vacuum concentration.The 1M NaOH aqueous solution (0.25mL) is added in the solution of resistates in DMF (0.9mL).At room temperature stirred solution 18 hours, then uses formic acid (0.25mL) acidifying.Through diatomite filtration crude mixture, and by preparation HPLC (tubing string: Atlantis, 19mm × 50mm, 5 μm, UV/MS, acidic conditions) purifying and evaporation (Genevac), obtain required acid.
The example of formula (I) compound prepared as initial substance with corresponding boric acid according to method mentioned above is enumerated in following table 29.
Table 29
Alkylation of phenol and saponification reaction subsequently
To (±)-1-(the fluoro-2-hydroxy-pheny of 5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate (14mg, 0.038mmol, 1.0 equivalents) and cesium carbonate (37mg, 0.115mmol, 3.0 equivalents) add ethyl bromoacetate (6 μ L, 0.057mmol, 1.5 equivalents) in suspension in DMF (1mL).At room temperature stirred reaction mixture 18 hours.With water (25mL) and AcOEt (30mL) diluted reaction mixture.Be separated each layer.By AcOEt (2 × 15mL) aqueous phase extracted.By water (1 × 10mL), the organic phase of the saturated NaCl aqueous solution (1 × 10mL) washing through merging, through MgSO 4dry and vacuum concentration.Resistates is dissolved in DMF (1mL), adds the 1M NaOH aqueous solution (1mL).At room temperature stir gained solution 18 hours.With formic acid (1.00mL) neutralization solution, filter, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
The example of formula (I) compound prepared as initial substance according to method corresponding phenol 30 mentioned above is enumerated in following table 30.
Table 30
Acid amides coupling and saponification reaction subsequently
TBTU (39mg is added in the solution of (2-methoxyphenoxy) acetic acid (22mg, 0.12mmol, 1.2 equivalents) in DMF (1mL), 0.12mmol, 1.2 equivalents) and DIPEA (51 μ L, 0.30mmol, 3.0 equivalents).At room temperature stir gained mixture 30 minutes.Add (±)-[the chloro-2-of 4-(2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-ethyl acetate hydrochloride (37mg, 0.10mmol, the 1.0 equivalents) solution in DMF (0.5mL).At room temperature stir the mixture 1 hour.Add the 1M NaOH aqueous solution (1mL) and at room temperature stir the mixture 30 minutes, then vacuum concentration.By preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and evaporation, obtain the required acid in white solid.
The example of formula (I) compound prepared as initial substance according to amine and the respective acids of method corresponding construction 2 mentioned above is enumerated in following table 31.
Table 31
Example 526:(±)-{ the chloro-2-of 4-[the fluoro-2-of 5-(3-indazole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid (C26H21N3O4ClF, MW=493.92)
DIPEA (0.12mL is sequentially added in the solution of 3-indazole-1-base-propionic acid (34mg, 0.17mmol, 1.2 equivalents) in DMF (4mL), 0.70mmol, 5.0 equivalents) and TBTU (54mg, 0.17mmol, 1.2 equivalents).At room temperature stir gained gained solution 30 minutes.Add containing (±)-[the chloro-2-of 4-(5-fluoro-2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-ethyl acetate hydrochloride (60mg, 0.14mmol, 1.0 equivalents) DMF (1mL) and at room temperature stir gained mixture 18 hours.Vacuum concentration reaction mixture.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration.Gained ester derivative to be dissolved in DMF (0.50mL) and to add the 1M NaOH aqueous solution (0.50mL).At room temperature stir gained solution 18 hours.With formic acid (1.0mL) souring soln, filter, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
LC-MS 1FA：t R=1.00min；[M+H] +=494.2。
Michael addition
By Potassium monofluoride 40 % by weight/aluminum oxide (218mg; 3.75mmol; 25 equivalents) be added into [2-((S)-2-acryl-2; 3-dihydro-1H-isoindole-1-base) the chloro-phenoxy group of-4-]-ethyl acetate (58mg; 0.15mmol; 1.0 equivalents) and the mixture of the fluoro-1H-indazole of 5-(25mg, 0.18mmol, 1.2 equivalents) in MeCN (1mL) in.Gained suspension is stirred 18 hours at 80 DEG C.Add formic acid (0.2mL).Filter reaction mixture and vacuum concentrated filtrate.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration, obtain the required product in white foam.
The example of formula (I) compound prepared as initial substance according to method mentioned above corresponding ethernamine 8 and corresponding heterocycle 9 is enumerated in following table 32.
Table 32
Urea formation and saponification reaction subsequently
To (±)-[the chloro-2-of 4-(2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-ethyl acetate hydrochloride (40mg, 0.11mmol, 1.00 equivalents) and NEt 3isocyanic acid 2-fluoro-methylbenzyl ester (17mg, 0.11mmol, the 1.05 equivalents) solution in MeCN (1mL) is added in (45 μ L, 0.33mmol, 3.00 equivalents) solution in MeCN (1mL).At room temperature stir the mixture 18 hours.Add the 1M NaOH aqueous solution (0.50mL) and at room temperature stirred solution 18 hours.With formic acid (about 1mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum (Genevac) concentrate, obtain required acid.
The example of formula (I) compound prepared as initial substance according to amine and the corresponding isocyanic ester of method corresponding construction 2 mentioned above is enumerated in following table 33.
Table 33
Alkylation of phenol and saponification reaction subsequently
To (±)-4, the chloro-1-of 5-bis-(5-chlorine-2-hydroxyl-phenyl)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate (25mg, 0.06mmol, 1.0 equivalents) and the solution of cesium carbonate (37mg, 0.11mmol, 2.0 equivalents) in DMF (1.0mL) in add ethyl bromoacetate (7.5 μ L, 0.07mmol, 1.2 equivalents).At room temperature stir gained solution 18 hours.Add the 1M NaOH aqueous solution (0.50mL).At room temperature stir the mixture 2 hours.With formic acid (0.50mL) neutralization solution, then by preparation HPLC (tubing string: Atlantis, 18mm × 50mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain required acid.
The example of formula (I) compound prepared as initial substance according to method corresponding phenol 30 mentioned above is enumerated in following table 34.
Table 34
The chloro-2-of example 560:{4-[(S)-2-((1R, 2R)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (C28H26NO4Cl, MW=475.97) and
The chloro-2-of example 561:{4-[(S)-2-((1S, 2S)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (C28H26NO4Cl, MW=47597)
By chiral preparative HPLC (tubing string: (R, R)-Whelk-01, 5 μm, 21.1mm × 250mm, Hept/EtOH+0.1%TFA 6:4, flow velocity is 16mL/min) be separated { the chloro-2-of 4-[(S)-2-(trans-2-o-tolyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (mixtures of 2 kinds of diastereomers), obtain { the chloro-2-of 4-[(S)-2-((1R, 2R)-2-o-tolyl-cyclopropyl carbonyl)-1, 2, 3, 4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (LC-MS 1FA:t r=1.15min, [M+H] +=476.3) and { the chloro-2-of 4-[(S)-2-((1S, 2S)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid (LC-MS 1FA:t r=1.18min, [M+H] +=476.3).
The chloro-2-{ of example 562:(4-(S)-2-[(1R, 2R)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C28H23NO4ClF3, MW=529.94) and
The chloro-2-{ of example 563:(4-(S)-2-[(1S2S)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C28H23NO4ClF3, MW=529.94)
By chiral preparative HPLC (tubing string: (R, R)-Whelk-01, 5 μm, 21.1mm × 250mm, Hept/EtOH+0.1%TFA 7:3, flow velocity is 16mL/min) be separated (the chloro-2-{ of 4-(S)-2-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (mixtures of 2 kinds of diastereomers), obtain (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (LC-MS 1FA:t r=1.17min, [M+H] +=530.3) and (the chloro-2-{ of 4-(S)-2-[(1S, 2S)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (LC-MS 1FA:t r=1.19min, [M+H] +=530.3).
The chloro-2-{ of example 564:(4-(S)-2-[(1R, 2R)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C27H23NO4Cl2, MW=496.39)
By chiral preparative HPLC (tubing string: Daicel, ChiralPak IA, 5 μm, 20mm × 250mm, Hept/EtOH+0.1%TFA 85:15, flow velocity is 16mL/min) be separated (the chloro-2-{ of 4-(S)-2-[trans-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (mixtures of 2 kinds of diastereomers), obtain (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (LC-MS 1FA:t r=1.17min, [M+H] +=496.2).
The chloro-2-{ of example 565:(4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C27H23NO4ClF, MW=479.93)
By chiral preparative HPLC (tubing string: Daicel, ChiralPak IA, 5 μm, 20mm × 250mm, Hept/EtOH+0.1%TFA 8:2, flow velocity is 16mL/min) be separated (the chloro-2-{ of 4-(S)-2-[trans-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (mixtures of 2 kinds of diastereomers), obtain (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (LC-MS 1FA:t r=1.12min, [M+H] +=480.3).
The chloro-2-{ of example 566:(4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (C27H23NO4ClF, MW=479.93)
By chiral preparative HPLC (tubing string: Daicel, ChiralPak IA, 5 μm, 20mm × 250mm, Hept/EtOH+0.1%TFA 75:25, flow velocity is 16mL/min) be separated (the chloro-2-{ of 4-(S)-2-[trans-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (mixtures of 2 kinds of diastereomers), obtain (the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1, 2, 3, 4-tetrahydro-isoquinoline-1-base }-phenoxy group)-acetic acid (LC-MS 1FA, t r=1.12min, [M+H] +=480.3).
Example 567:(S)-1-(the chloro-2-of 5-(2-cyanogen amino-2-oxoethoxy) phenyl)-3,4--dihydro-isoquinoline-2 (1H)-benzyl formates (C26H22N3O4Cl, MW=475.93)
To (S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (138mg, 0.30mmol, 1.0 equivalents), cyanamide (16mg, 0.36mmol, 1.2 equivalents) and NEt 3hATU (137mg, 0.36mmol, 1.2 equivalents) is added in (84 μ L, 0.60mmol, 2 equivalents) solution in DMF (3.3mL).At room temperature stirred reaction mixture 1 hour.By preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) purified mixture and evaporation, obtain by NEt 3the pale yellow oil polluted.The product of pollution to be dissolved in again in AcOEt and with the 1M HCl aqueous solution and saturated NaCl solution washing.Through MgSO 4dry organic phase, filters and vacuum concentration, obtains the required product in faint yellow oily.
LC-MS 1FA：t R=1.27min；[M+H] +=476.1。
Example 568:(S)-1-[the chloro-2-of 5-(2-oxo-2-trifluoromethanesulphonylamino-oxyethyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H22N2O6ClF3S, MW=582.98)
To (S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (138mg, 0.30mmol, 1.0 equivalents) add trifluoromethanesulfonamide (47mg, 0.30mmol, 1.0 equivalents), HATU (125mg in solution in DMF (1.2mL), 0.33mmol, 1.1 equivalents), DIPEA (103 μ L, 0.60mmol, 2.0 equivalents) and DMAP (spatula point).Gained mixture is stirred 18 hours at 50 DEG C.Then by preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) purified mixture and evaporation, the pale solid polluted by some DIPEA is obtained.The product of pollution to be dissolved in again in AcOEt and with the 1M HCl aqueous solution and saturated NaCl solution washing.Through MgSO 4dry organic phase, filters and vacuum concentration, obtains the required product in pale solid shape.
LC-MS 1FA：t R=1.19min；[M+H] +=583.1。
Example 569:(S)-1-(5-chlorine-2-hydroxyl carbamyl methoxyl group-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H23N2O5Cl, MW=466.92)
To (S)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (144mg, 0.30mmol, 1.0 equivalents) add azanol (50 % by weight aqueous solution, 1.5mL) in ice cold solution in Virahol (1.5mL).Remove ice bath and at room temperature stirred reaction mixture 18 hours.Concentrated reaction mixture to half and add water (5mL).Filter gained suspension, wash with water and drying under high vacuum, obtain the required product in white solid.
LC-MS 1FA：t R=1.13min；[M+H] +=467.3。
Example 570:(±)-1-[the chloro-2-of 5-(1H-TETRAZOLE-5-ylmethoxy)-phenyl]-3,4--dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H22N5O3Cl, MW=475.94)
By sodium azide (49mg, 0.75mmol, 3 equivalents) be added into (±)-1-(the chloro-2-Cyanomethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (108mg, 0.25mmol, 1 equivalent) in solution in DMF (4.6mL).Reacting by heating mixture to 100 DEG C, and stir 18 hours under Bi Wendu.Make mixture be cooled to room temperature, and by preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) purifying and evaporation (genevac), obtain the required product in white solid.
LC-MS 1FA：t R=1.21min；[M+H] +=476.3。
Example 571:(S)-1-[the chloro-2-of 5-(5-oxo-4,5-dihydro-[and 1,3,4] oxadiazole-2-ylmethoxies)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H22N3O5Cl, MW=491.93)
To (S)-1-(the chloro-2-hydrazinocarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (137mg, 0.29mmol, 1.0 equivalents) and NEt 31,1'-carbonyl dimidazoles (72mg, 0.44mmol, 1.5 equivalents) is added in (82 μ L, 0.59mmol, 2.0 equivalents) ice cold solution in THF (3mL).At room temperature stirred reaction mixture 1 hour.Vacuum removes solvent.Resistates to be dissolved in DMF (2.4mL) again and by preparation HPLC (tubing string: Waters X-Bridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and evaporation, to obtain the required product in white foam.
LC-MS 1FA：t R=1.14min；[M+H] +=492.3。
Example 572:(±)-1-[the chloro-2-of 5-(5-oxo-4,5-dihydro-[1,2,4] oxadiazole-3-ylmethoxies)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H22N3O5Cl, MW=491.93)
At 120 DEG C, (±)-1-[the chloro-2-of 5-(N-hydroxy formamidine ylmethoxy)-phenyl]-3 is heated under microwave irradiation, 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (93mg, 0.20mmol, 1.0 equivalents), 1,1'-carbonyl dimidazoles (39mg, 0.24mmol, 1.2 equivalents) and 1,8-diaza-bicyclo [5.4.0] 11-7-alkene (33 μ L, 0.22mmol, 1.1 equivalents) solution in THF (2.7mL) 20 minutes.Make mixture be cooled to room temperature and be allocated between AcOEt and the 0.5M HCl aqueous solution.By the 0.5M HCl aqueous solution and saturated NaCl solution washing organic phase, through MgSO 4drying, filters and vacuum concentration.By preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration, obtain the required product in white solid.
LC-MS 1FA：t R=1.21min；[M+H] +=492.3。
Example 573:(±)-1-[the chloro-2-of 5-(3-hydroxyl-isoxazole-5-base methoxyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C27H23N2O5Cl, MW=490.94)
To (±)-5-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxymethyl]-isoxazol-3-ol (49mg, 0.138mmol, 1.0 equivalents) and the ice cold solution of NEt3 (58 μ L, 0.414mmol, 3.0 equivalents) in DCM (3.8mL) in dropwise add chloroformic acid benzyl ester (23 μ L, 0.152mmol, 1.1 equivalents).When the addition is complete, cooling bath is removed and at room temperature stirred suspension 4 hours.React with 1M aqueous citric acid solution (3.8mL) cancellation.Be separated each layer.With DCM aqueous phase extracted (3 times).The organic phase of vacuum concentration through merging.Resistates to be dissolved in DMF again and by preparation HPLC (tubing string: WatersXBridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and evaporation (genevac), to obtain the required product in faint yellow solid shape.
LC-MS 1TFA：t R=1.16min；[M+H] +=491.2。
Synthesis precursor and intermediate
The general method of synthesis nitre vinylbenzene 22.
Phenyl aldehyde 23 (40.00mmol, 1 equivalent) is dissolved in Nitromethane 99Min. (23.8mL).Add molecular sieve 4A (766mg), butylamine (0.47mL, 4.72mmol, 0.12 equivalent) and acetic acid (0.47ml, 8.16mmol, 0.20 equivalent) and heated mixt to 95 DEG C maintains 1 hour.Mixture is transferred in new flask to remove molecular sieve.Vacuum removes solvent.By CC (SiO 2, eluent: Hept/AcOEt) and Purification, obtain required nitre vinylbenzene.
The nitre vinylbenzene 22 prepared as initial substance with corresponding phenyl aldehyde 23 according to method mentioned above is enumerated in following table 35.
Table 35
Prepare the general method of phenylethylamine (or corresponding hydrochloride) 21.
Under ice-cooling by H 2sO 4(2.870mL) LiAlH of stirring is dropwise added into 4in (4.30g, 107.6mmol, 4.46 equivalents) suspension in THF (162mL).After stirring 20 minutes, in 20 minutes, dropwise add nitre vinylbenzene 22 (24.1mmol, the 1.00 equivalents) solution in THF (17mL) under ice-cooling.After 10 min, remove cooling bath, and by use heat gun make mixture gradually heating direct gradually boil to mixture.After 5 minutes, then cooling mixture to 0 DEG C.By dropwise adding iPrOH (18mL), add the careful cancellation reaction of the 2M NaOH aqueous solution (13mL) afterwards.Filter gained suspension and use THF flush cake.Vacuum concentrated filtrate obtains required phenylethylamine.
Unhindered amina is dissolved in the Et containing iPrOH (3mL) 2in O (88mL), and with the Et of 2M HCl 2o solution (46mL) acidifying.Filter gained suspension.Use Et 2o rinses white solid and high vacuum dry.Namely required phenylethylamine salt use without being further purified.
The phenylethylamine 21 and phenethylamine hydrochloride 21 prepared as initial substance according to the corresponding nitre vinylbenzene 22 of method mentioned above is enumerated in following table 36.
Table 36
Synthesis 2-methyl-2-phenyl-propylamine (C10H15N, MW=149.24)
Step 1: to benzyl cyanide (2.34mL at 0 DEG C, 20.0mmol, 1.0 equivalents) and NaOH (3.22g, 80.5mmol, 4.0 equivalents) in DMSO (19mL) with the suspension in the mixture of water (3.2mL), dropwise add methyl iodide (5.0mL, 80.0mmol, 4.0 equivalents).At room temperature stir gained mixture 18 hours.Mixture is made to be allocated in Et 2between O (125ml) and water (125ml).Be separated each layer and use Et 2o (2 × 50mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration, obtains 2-methyl-2-phenyl-propionitrile.Namely product uses without being further purified.
Step 2: at N 2lower through 30 points of clockwise LAH (1.43g, 35.7mmol, 1.5 equivalents) in anhydrous Et 22-methyl-2-phenyl-propionitrile (3.46g, 23.8mmol, 1.0 equivalents) is dropwise added in anhydrous Et in ice-cold suspension in O (70.0mL) 2solution in O (3.0mL).After 30 minutes, remove cooling bath and at room temperature stir the mixture 3 hours.Mixture is cooled to 0 DEG C again and then adds the careful cancellation of the 2M NaOH aqueous solution (20mL) by dropwise adding iPrOH (35mL).THF flush cake is used via diatomite filtration gained suspension.Vacuum concentrated filtrate.Resistates is allocated between DCM (125ml) and the 1M NaOH aqueous solution (125ml).Be separated each layer and by DCM (2 × 50mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 25mL) washing through merging, through MgSO 4dry and vacuum concentration.Namely gained 2-methyl-2-phenyl-propylamine uses without being further purified.
LC-MS 2：t R=0.39min；[M+H] +=150.2(Waters X-bridge)。
The general method of synthesis 3,4-dihydro-isoquinoline 11.
Method A: stir phenethylamine hydrochloride 21 (12.45mmol at 70 DEG C, 1.0 equivalents), triethylamine (3.47mL, 24.89mmol, 2.0 equivalents) and ethyl formate (1.01g, 13.69mmol, 1.1 equivalents) mixture 4 hours.Make reaction mixture be cooled to room temperature and be allocated between AcOEt (65mL) and water (65mL).Be separated each layer.Organic phase is washed, through MgSO with water (1 × 65mL), the saturated NaCl aqueous solution (1 × 65mL) 4dry and vacuum concentration, obtains corresponding methane amide.Methane amide is dissolved in DCM (125mL).Add oxalyl chloride (1.18mL, 13.69mmol, 1.1 equivalents).At room temperature stir the mixture 30 minutes, be then cooled to-10 DEG C.Anhydrous Ferric Chloride (III) (2.42g, 14.94mmol, 1.2 equivalents) is added in cold mixt.Make gained mixture slowly be warming up to room temperature and at room temperature stir 18 hours.React with the 2M HCl aqueous solution (125mL) cancellation and at room temperature stir biphasic system 1 hour.Be separated each layer.By DCM (1 × 65mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 65mL) washing through merging, through MgSO 4drying, and vacuum concentration, get is Dao oxazole and intermediate.Jiang oxazole and intermediate is dissolved in MeOH (142mL) and dense H 2sO 4(7.5mL) in.Backflow gained mixture 3 hours.Mixture is made to be cooled to room temperature and vacuum concentration.Resistates is allocated between water (65mL) and AcOEt (65mL).Be separated each layer.By the 2M HCl aqueous solution (2 × 30mL) extracted organic phase.Use 25%NH 3alkalize through merge three acid aqueous phases and extract with DCM (3 × 65mL).By the organic phase of the saturated NaCl aqueous solution (1 × 65mL) washing through merging, through MgSO 4drying, and vacuum concentration, obtain required 3, the 4-dihydro-isoquinolin in yellow solid.Namely resistates uses without being further purified.
3, the 4-dihydro-isoquinolines 11 prepared as initial substance according to the corresponding phenylethylamine of method mentioned above (or corresponding hydrochloride) 21 are enumerated in following table 37.
Table 37
Method B: synthesis 3,4-dihydro-isoquinolin (C9H9N, MW=131.18): at room temperature careful through 20 minutes and add N-bromo-succinimide (9.89g by part, 55.0mmol, 1.1 equivalents) to 1,2,3, in the solution of 4-tetrahydroisoquinoline (6.34mL, 50.0mmol, 1.0 equivalents) in DCM (130mL).At room temperature stir the mixture 1.5 hours.Add the 30%NaOH aqueous solution (35mL) and at room temperature stir the mixture 2 hours.Be separated organic layer and wash with water (1 × 70mL).With the 10%HCl aqueous solution (2 × 80mL) extraction product.Wash the acid extract thing through merging with DCM (1 × 80mL) and use 25%NH 3alkalization.Gained mixture is extracted with DCM (2 × 80mL).Through MgSO 4the dry organic extract through merging, filters and vacuum concentration, obtains 3, the 4-dihydro-isoquinolines in orange oily.Namely product uses without being further purified.
LC-MS 2：t R＝0.23min；[M+H] +=132.1。
The general method of tetrahydrobiopterin synthesis isoquinoline 99.9 13.
Method A: at room temperature under argon atmosphere, chloroformic acid benzyl ester (0.33mL, 2.17mmol, 1.0 equivalents) is added in 3,4-dihydro-isoquinoline 11 (2.17mmol, the 1.0 equivalents) solution in MeCN (4mL).After 30 minutes of stirring, add phenol 12 (2.17mmol, 1.0 equivalents) and stir the mixture at 70 DEG C 4 days.Reaction mixture is made to be cooled to room temperature, with AcOEt dilution, with the 2M HCl aqueous solution, water and saturated NaCl solution washing, through MgSO 4drying, filters and vacuum concentration.By flash master (Hept/AcOEt) purified product, produce the required tetrahydroisoquinoline 13 in white foam.
To enumerate the tetrahydroisoquinoline 13 prepared as initial substance with corresponding 3,4-dihydro-isoquinolines 11 and phenol 12 according to method mentioned above in following table 38.
Table 38
Method B: add tert-Butyl dicarbonate (1.09g, 5.0mmol, 1.0 equivalents) in 3,4-dihydro-isoquinoline 11 (5.0mmol, the 1.0 equivalents) solution in MeCN (15mL).At room temperature stir gained solution 2 hours.Add phenol 12 (5.0mmol, 1 equivalent) and stir the mixture at 60 DEG C 6 days.Vacuum concentration reaction mixture.Resistates is diluted and with the 10%HCl aqueous solution (1 × 25mL), saturated NaHCO with AcOEt (50mL) 3the aqueous solution (1 × 25mL), water (2 × 25mL), the saturated NaCl aqueous solution (1 × 25mL) wash, through MgSO 4dry and vacuum concentration.By flash master (heptane is to heptane+AcOEt for tubing string: 100g, flow velocity: 40mL/min) Purification, produce the required tetrahydroisoquinoline 13 in white foam.
To enumerate the tetrahydroisoquinoline 13 prepared as initial substance with corresponding 3,4-dihydro-isoquinolines 11 and phenol 12 according to method mentioned above in following table 39.
Table 39
The synthesis 2-allyloxy-1-fluoro-benzene of bromo-4-(C9H8OBrF, MW=231.06) and the fluoro-benzene (C9H8OBrF, MW=231.06) of the bromo-3-of 1-allyloxy-2-
To the bromo-5-fluorophenol of 2-(2.01g, 10.5mmol, 1.00 equivalents) and Anhydrous potassium carbonate (1.60g, 11.6mmol, 1.10 equivalents) add allyl bromide 98 (0.97mL, 11.1mmol, 1.05 equivalents) in mixture in acetone (25mL).Heated mixt, to backflow, maintains 4 hours.Reaction mixture is made to be cooled to room temperature and in impouring water (150mL).Gained mixture is extracted with DCM (2 × 200mL).Through MgSO 4dry organic phase through merging and vacuum concentration.By falsh master (flow velocity: 40mL/min, heptane is to heptane+AcOEt) Purification, produce in colorless oil through protection phenol.
LC-MS 3:t r=0.92min; [M+H] +=unionized.
Follow same program, but with the bromo-3-fluorophenol of 2-for initiator, obtain the fluoro-benzene of the 1-bromo-3-of allyloxy-2-.
LC-MS 3:t r=0.92min; [M+H] +=unionized.
Synthesis (±)-1-(the fluoro-phenyl of 2-allyloxy-4-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H24NO3F, and (±)-1-(the fluoro-phenyl of 2-allyloxy-6-)-3 MW=417.48), 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H24NO3F, MW=417.48)
At N 2the lower fluoro-benzene (462mg of the bromo-4-of 2-allyloxy-1-to cooling at-20 DEG C, 2.00mmol, 2.0 equivalents) dropwise add THF (1:1) (about 14% in the THF) (320mg of chloride containing isopropyl-magnesium-lithium chloride mixture in solution in THF (2mL), 2.20mmol, 2.2 equivalents).Stir the mixture at-20 DEG C 30 minutes, and stir 2 hours at 0 DEG C again, and at room temperature stir 6 hours again.→ grignard solution A
Chloroformic acid benzyl ester (0.15mL, 1.00mmol, 1.0 equivalents) is added in the solution of 3,4-dihydro-isoquinolin (131mg, 1.00mmol, 1.0 equivalents) in THF (5mL).At room temperature stir gained mixture 30 minutes.Cooling reactant to 0 DEG C and dropwise add grignard solution A.Stir the mixture at 0 DEG C 1 hour and at room temperature stir 18 hours again.Use 1M NH 4the Cl aqueous solution (50mL) and with the careful cancellation reaction of AcOEt (50mL).Via diatomite filtration gained suspension and by water and AcOEt flush cake.Be separated each layer and by AcOEt (2 × 50mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 50mL) washing through merging, through MgSO 4dry and vacuum concentration.
By preparation HPLC (tubing string Water X-bridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) Purification and vacuum concentration.
LC-MS 2：t R=1.05min；[M+H] +=417.8。
Follow same program, but with the fluoro-benzene of the bromo-3-of 1-allyloxy-2-for initiator, obtain (±)-1-(the fluoro-phenyl of 2-allyloxy-6-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate.
LC-MS 3：t R=1.04min；[M+H] +=417.9。
Fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C28H24N2O5F2, MW=506.50) of synthesis (±)-1-(5-cyano group-2-ethoxycarbonylmethoxy-phenyl)-6,7-bis-
At room temperature to (±)-1-(the bromo-2-ethoxycarbonylmethoxy-phenyl of 5-)-6,7-bis-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (126mg, 0.23mmol, 1.00 equivalents) add poly-(methyl hydrogen siloxane) (5 μ L) in solution in N,N-dimethylacetamide (0.45mL).Reacting by heating mixture to 120 DEG C and add ginseng (dibenzalacetone) two palladium (0) (4.5mg, 0.005mmol, 0.002 equivalent), then 1 is added, 1'-pair-(diphenyl phosphine)-ferrocene (3.4mg, 0.006mmol, 0.027 equivalent).Afterwards, zinc cyanide (6.6mg, 0.056mmol, 0.25 equivalent) is added.At 150 DEG C, gained mixture is stirred 25 minutes in microwave.Add zinc cyanide (3.3mg again, 0.028mmol, 0.13 equivalent), ginseng (dibenzalacetone) two palladium (0) (2.3mg, 0.002mmol, 0.001 equivalent) and 1,1'-pair-(diphenyl phosphine)-ferrocene (1.7mg, 0.003mmol, 0.014 equivalent).At 150 DEG C, gained mixture is stirred 25 minutes in microwave.With AcOEt diluted reaction mixture and through diatomite filtration.Wash filtrate with water, through MgSO 4drying, filters and vacuum concentration.By CC (SiO 2, eluent: Hept/AcOEt) and Purification, produce the carbonitrile derivatives in faint yellow oily.
LC-MS 2：t R=0.97min；[M+H] +=507.3。
The general method of the ester of composite structure 10.
At room temperature ethyl bromoacetate (0.44mL, 3.97mmol, 1.5 equivalents) is added into phenol 13 (2.65mmol, 1.0 equivalents) and K 2cO 3in (1.10g, 7.95mmol, 3.0 equivalents) solution in DMF (9mL).At room temperature stir the mixture 2 hours.With AcOEt and water diluted reaction mixture.Be separated each layer and with AcOEt aqueous phase extracted (2 times).The organic phase through merging with water and saturated NaCl solution washing, through MgSO 4drying, filters and vacuum concentration.By CC (SiO 2, Hept/AcOEt) and purification of crude product, produce required ethyl ester.
The ester of the structure 10 prepared as initial substance with corresponding tetrahydroisoquinoline 13 according to method mentioned above is enumerated in following table 40.
Table 40
Fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C27H25NO5ClF, MW=497.95) of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6-
To (±)-[the chloro-2-of 4-(6-fluoro-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (900mg, 2.25mmol, 1.0 equivalents) and DIPEA (1.16mL, 6.75mmol, 3.0 equivalents) dropwise add chloroformic acid benzyl ester (0.43mL, 2.92mmol, 1.3 equivalents) in ice cold solution in DCM (30mL).When the addition is complete, cooling bath is removed and at room temperature stirred solution 3 hours.React with 1M aqueous citric acid solution (25mL) cancellation.Be separated each layer.By DCM (3 × 50mL) aqueous phase extracted.Through MgSO 4dry organic phase through merging and vacuum concentration.By flash master (heptane+10%EtOAc is to heptane+50%EtOAc for tubing string: 50g, flow velocity: 40mL/min) Purification, produce title compound.
LC-MS 3：t R=1.05min；[M+H] +=498.4。
The general method of the ester of composite structure 10.
Step 1:(S)-2-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate (C 11H14O5S, MW=258.29)
To (S)-(-)-methyl lactate (4.6mL, 47.07mmol, 1.0 equivalents) add trimethylamine hydrochloride (450mg in ice cold solution in MeCN (25mL), 4.71mmol, 0.1 equivalent) and triethylamine (7.35mL, 52.81mmol, 1.1 equivalents).Slowly added Tosyl chloride (9.06g, 47.07mmol, the 1.0 equivalents) solution in MeCN (25mL) through 40 minutes at 0 DEG C.At N at 0 DEG C 2lower stirred reaction mixture 1 hour.Wash via diatomite filtration mixture MeCN.Vacuum concentrated filtrate, then uses water (30mL) to dilute, and uses Et 2o (3 × 60mL) extracts.Through MgSO 4the dry organic layer through merging, filters and vacuum concentration, obtains the tosylate in yellow liquid.Product is used for next step with crude form.
LC-MS 2：t R＝0.84min；[M+H] +=259.1。
With (R)-(+)-methyl lactate for initiator, obtain (R)-2-(toluene-4-alkylsulfonyl oxygen base)-methyl propionate (C11H14O5S, MW=258.29).
Step 2: to (±)-1-(the fluoro-2-hydroxy-pheny of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (500mg, 1.33mmol, 1.0 equivalents) add tosylate (1.33mmol in solution in MeCN (5mL), 1.0 equivalents) and Anhydrous potassium carbonate (366mg, 2.65mmol, 2.0 equivalents), and heated mixt to 65 DEG C maintains 18 hours.Make mixture be cooled to room temperature, and use Et 2o extracts (2 times), through MgSO 4drying, filters and vacuum concentration.By FC (SiO 2, eluent: Hept/AcOEt) and purification of crude product, produce the ester of the form of mixtures in 2 kinds of diastereomers.
The ester of the structure 10 prepared as initial substance according to the corresponding tetrahydroisoquinoline 13 of method mentioned above and corresponding tosylate is enumerated in following table 41.
Table 41
The amine of composite structure 2 or the general method of corresponding hydrochloride
Method A: at N 2lower to (±)-1-(the fluoro-phenyl of 2-ethoxycarbonylmethoxy-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (760mg, 1.64mmol, 1.0 equivalents) add palladium/activated carbon (10 % by weight, 76mg) in solution in EtOH.Flask is carefully vacuumized and uses H 2refill (3 times).At room temperature at H 2black suspension is stirred 18 hours under atmosphere.Through diatomite filtration black suspension.Diatomite is rinsed with EtOH.Vacuum concentrated filtrate.Crude mixture is dissolved in 4M HCl dioxane solution (10mL).At room temperature stir gained solution 30 minutes, then vacuum concentration.New crude salt to be dissolved in EtOH and vacuum concentration (3 times), to obtain required salt.
The hydrochloride of the structure 2 that the tetrahydroisoquinoline protected according to the Cbz of method corresponding construction 10 mentioned above is prepared as initial substance is enumerated in following table 42.
Table 42
Method B: to (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (1.27g, 2.84mmol, 1.0 equivalents) add 4M HCl dioxane solution (12mL) in ice cold solution in DCM (5mL).At room temperature stir gained solution 7 hours.Vacuum concentration reaction mixture.Resistates and EtOH evaporate jointly (3 times).Use Et 2o/ pentane wet-milling product obtains title salt.
The hydrochloride of the structure 2 that the tetrahydroisoquinoline protected according to the Boc of method corresponding construction 10 mentioned above is prepared as initial substance is enumerated in following table 43.
Table 43
Method C: add containing 33% hydrobromic acetic acid (2.5mL) in the solution of the tetrahydroisoquinoline (1.04mmol, 1.0 equivalents) protected to the Cbz of structure 10 in AcOH (10mL).At room temperature stir the mixture 1 hour.Vacuum concentration reaction mixture.By flash master, (tubing string: 100g, flow velocity: 45mL/min, heptane is to AcOEt+10%NEt 3) Purification.By gained amine solvent in EtOH (20mL) and add Acetyl Chloride 98Min. (0.11mL, 1.48mmol, 1.4 equivalents).Backflow gained solution 2 hours, is then cooled to room temperature, and vacuum concentration, obtain required hydrochloride.
The hydrochloride of the structure 2 that the tetrahydroisoquinoline protected according to the Cbz of method corresponding construction 10 mentioned above is prepared as initial substance is enumerated in following table 44.
Table 44
Method D:(±)-[the chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (C19H20NO3Cl, MW=345.83): to (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (1.03g, 2.15mmol, 1.0 equivalents) add containing 33% hydrobromic acetic acid (7.5mL) in solution in AcOH (30mL).At room temperature stir the mixture 1 hour.Vacuum concentration reaction mixture.By flash master, (tubing string: 100g, flow velocity: 45mL/min, heptane is to AcOEt+10%NEt 3) Purification generation title amine.LC-MS 3：t R=0.71min；[M+H] +=346.3。
Method E:(±)-[the fluoro-2-of 4-(6-fluoro-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (C19H19NO3F2, MW=347.36): to the fluoro-1-of the bromo-6-of (±)-5-(the fluoro-2-hydroxy-pheny of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (50mg, 0.11mmol, 1.0 equivalents) and Cs 2cO 3ethyl bromoacetate (18 μ L, 0.16mmol, 1.5 equivalents) is added in (104mg, 0.32mmol, 3.0 equivalents) solution in DMF (1mL).At room temperature stir gained solution 18 hours.Evaporating solvent and by mixture impouring water and with DCM extraction (3 times).Wash with water through merge extract and through MgSO 4dry.At N 2down in the solution of resistates in EtOH (4mL), add palladium/activated carbon (10 % by weight, 10mg).Flask is vacuumized and uses H 2backfill (3 times).At room temperature at H 2black suspension is stirred 18 hours under atmosphere.Via diatomite filtration suspension, rinse diatomite with EtOH, and vacuum concentrated filtrate.By preparation HPLC (tubing string: Waters X-Bridge, 19mm × 50mm, 10 μm, UV/MS, alkaline condition) Purification, obtain title amine.
LC-MS 3：t R=0.62min；[M+H] +=348.2。
Synthesis (the chloro-2-1 of (S)-4-, 2,3,4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate (C19H20NO3Cl, MW=345.83)
To (S)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (790mg, 1.77mmol, 1.0 equivalents) add 4M HCl dioxane solution (7.4mL) in ice cold solution in DCM (3mL).At room temperature stir gained solution 1.5 hours.Vacuum concentration reaction mixture.Resistates and EtOH evaporate jointly (3 times).Dense H is added in the solution of resistates in EtOH (2mL) 2sO 4(0.18mL).At room temperature stirred solution 18 hours.Add water and the 5%NaOH aqueous solution, and use Et 2o (3 × 10mL) extracts mixture.Through MgSO 4the dry organic phase through merging, filters and vacuum concentration, obtains required product.
LC-MS 3：t R=0.67min；[M+H] +=346.1。
Synthesis [the chloro-2-of 4-(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of (S)-6-)-phenoxy group]-ethyl acetate (C19H19NO3ClF, MW=363.82)
To (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6-fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (640mg, 1.38mmol, 1 equivalent) add 4MHCl dioxane solution (5.5mL) in ice cold solution in EtOH (2.5mL).At room temperature stir gained solution 3 hours.Vacuum concentration reaction mixture.Resistates is made to be allocated in AcOEt and saturated NaHCO 3between the aqueous solution.Be separated each layer and use AcOEt aqueous phase extracted.The organic phase of vacuum concentration through merging obtains unhindered amina.
LC-MS 3：t R=0.73min；[M+H] +=364.2。
Synthesis (±)-[2-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate (C19H21NO3, MW=311.15)
At N 2lower to (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-t-butyl formate (446mg, 1.0mmol, 1.0 equivalents) add palladium/activated carbon (10 % by weight, 106mg) in solution in EtOH (4.8mL).Flask is carefully vacuumized and uses H 2refill (3 times).At H at 50 DEG C 2black suspension is stirred 48 hours under atmosphere.Through diatomite filtration black suspension.Diatomite is rinsed with EtOH.Vacuum concentrated filtrate.4M HCl dioxane solution (2.6mL) is added in the ice cold solution of resistates in DCM (1.8mL).At room temperature stir gained solution 18 hours.Vacuum concentration reaction mixture.Resistates and EtOH evaporate jointly (3 times).Resistates to be dissolved in DMF (2mL) again and by preparation HPLC (tubing string: Atlantis, 19mm × 30mm, 5 μm, UV/MS, acidic conditions) purifying and evaporation, to obtain the required amine in yellow oily.
LC-MS 3：t R=0.69min；[M+H] +=312.1。
Fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C26H23NO3ClF, MW=451.92) of synthesis (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-6-
Step 1: to fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (150mg, 0.28mmol, 1.00 equivalents) and the K of the bromo-1-of (±)-5-(5-chlorine-2-hydroxyl-phenyl)-6- 2cO 3allyl bromide 98 (26 μ L, 0.29mmol, 1.05 equivalents) is added in (43mg, 0.31mmol, 1.10 equivalents) mixture in acetone (0.7mL).In sealed vial, heated mixt to 60 DEG C maintains 18 hours.Reaction mixture is made to be cooled to room temperature and in impouring water (4mL).Mixture is extracted with DCM (2 × 5mL).Through MgSO 4the dry organic phase through merging, filters and vacuum concentration.By flash master (tubing string: 10g, flow velocity: 15mL/min, heptane is to heptane+10%AcOEt) partial purification resistates, produce fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of (±)-1-(the chloro-phenyl of 2-allyloxy-5-) the bromo-6-of-5-in colorless oil.
Step 2: at N 2lower (±)-1-(the chloro-phenyl of 2-allyloxy-5-) the bromo-6-of-5-fluoro-3 to cooling at-20 DEG C, 4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (90mg, 0.14mmol, 1.00 equivalents) dropwise add THF (0.32mL containing 14% isopropyl-magnesium chloride-lithium chloride mixture in solution in THF (0.28mL), 0.14mmol, 1.00 equivalents).Stir the mixture at 0 DEG C and be slowly warming up to room temperature through 2.5 hours.Use 1M NH 4the Cl aqueous solution (10mL) and with the careful cancellation reaction of AcOEt (10mL).Via diatomite filtration gained suspension and by water and AcOEt flush cake.Be separated each layer and by AcOEt (2 × 10mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 10mL) washing through merging, through MgSO 4drying, filters and vacuum concentration.By flash master (tubing string: 10g, flow velocity: 15mL/min, heptane is to heptane+10%AcOEt) Purification, produce fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-6-in colorless oil.
LC-MS 3：t R=1.07min；[M+H] +=452.1。
The bromo-benzyl ester (C27H25NO5BrCl, MW=558.85) of synthesis (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-
To (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (836mg, 2.00mmol, 1.0 equivalents) and DIPEA (0.86mL, 5.00mmol, 2.5 equivalents) add carbonic acid 2-bromo-benzyl ester 2,5-dioxo-pvrrolidin-1-base ester (787mg in solution in DCM (30mL), 2.40mmol, 1.2 equivalents).At room temperature stirred reaction mixture 2 hours.React with 1M aqueous citric acid solution (30mL) cancellation.Be separated each layer.With DCM aqueous phase extracted (3 times).Through MgSO 4the dry organic phase through merging, filters and vacuum concentration.Dense H is added in the solution of previous mixture in EtOH (1.1mL) 2sO 4(0.10mL).At room temperature stir gained solution 3 hours.Add water and the 5%NaOH aqueous solution, and extract mixture (3 times) with DCM.Through MgSO 4the dry organic phase through merging, filters and vacuum concentration, obtains the required product in faint yellow oily.
LC-MS 3：t R=1.06min；[M+H] +=560.0。
The general synthesis of ethernamine 8.
To (±)-[chloro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group] sequentially add acrylate chloride (0.98mL in the ice cold solution of-ethyl acetate hydrochloride (4.57g, 10.6mmol, 1.0 equivalents) in DCM (43mL), 11.7mmol, 1.1 equivalents) and DIPEA (3.99mL, 23.3mmol, 2.2 equivalents).Stir the mixture at 0 DEG C 1 hour.With DCM (200mL) and with 1M aqueous citric acid solution (1 × 200mL) diluting reaction thing.Be separated each layer.By DCM (2 × 200mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 200mL) washing through merging, through MgSO 4drying, filters and vacuum concentration.By flash master (heptane+20%AcOEt is to heptane+52%AcOEt for tubing string: 100g, flow velocity: 45mL/min) Purification, produce required ethernamine derivative.
The ethernamine 8 prepared as initial substance according to the amine of method corresponding construction 2 mentioned above is enumerated using following table 45.
Table 45
The general method of synthesizing carbonate ester 5
To 2-bromobenzene methyl alcohol (2.83g, 15.0mmol, 1.0 equivalents) and DMAP (916mg, 7.5mmol, 0.5 equivalent) add carbonic acid N in solution in MeCN/DCM 1:1 (45mL), N'-bis-succimide ester (3.84g, 15.0mmol, 1.0 equivalents).At room temperature stir the mixture 18 hours.Use H 2o (1 × 45mL), the saturated NaCl aqueous solution (1 × 45mL) purging compound, through MgSO 4drying, filters and vacuum concentration.Resistates is from iPrOH recrystallize.
The carbonic ether 5 prepared as initial substance with corresponding phenylcarbinol 6 according to method mentioned above is enumerated in following table 46.
Table 46
The general method of synthesis isoindoline 28
The hexane solution (0.80mL, 2.0mmol, 1.0 equivalents) of 2.5M butyllithium is added in the solution of the 2-bromobenzyl chlorine (424mg, 2.0mmol, 1.0 equivalents) of cooling in THF (15mL) at-78 DEG C.Gained yellow solution is stirred 20 minutes at-78 DEG C.(±)-2-methyl-propan-2--sulfinic acid 1-(the chloro-phenyl of 2-allyloxy-5-)-methylene amide (600mg, 2.0mmol, 1.0 equivalents) solution in THF (5mL) is dropwise added at-78 DEG C.At-78 DEG C, stir dark yellow solution 1 hour and at room temperature stir 1 hour again.Add H 2o (20mL) and be separated each layer.Use Et 2o (3 × 20mL) aqueous layer extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 20mL) washing through merging, through MgSO 4dry and vacuum concentration.The required isoindoline 28 in offwhite solid is produced by flashmaster (heptane is to heptane+30%AcOEt for tubing string: 100g, flow velocity: 45mL/min) Purification.
The isoindoline 28 prepared as initial substance with corresponding 2-bromobenzyl chlorine derivative 26 according to method mentioned above is enumerated in following table 47.
Table 47
Synthesis (±)-5-methyl-propan-2--sulfinic acid 1-(the chloro-phenyl of 2-allyloxy-5-)-methylene amide (C14H18NO2ClS, MW=299.82)
Step 1: to 5-chloro-salicylic aldehyde (8.20g, 52.37mmol, 1.00 equivalents) and Anhydrous potassium carbonate (8.69g, 62.85mmol, 1.20 equivalents) add allyl bromide 98 (4.7mL in mixture in DMF (100mL), 54.99mmol, 1.05 equivalents).Heated mixt 18 hours at 50 DEG C.Reaction mixture is made to be cooled to room temperature and in impouring water (150mL).Gained mixture is extracted with DCM (2 × 200mL).Through MgSO 4dry organic phase through merging and vacuum concentration, obtain the chloro-phenyl aldehyde of 2-allyloxy-5-.Namely product uses without being further purified.
Step 2: to the chloro-phenyl aldehyde (8.55g of 2-allyloxy-5-, 43.48mmol, 1.0 equivalents) and 2-methyl-2-propanesulfinamide (6.86g, 56.64mmol, 1.3 equivalents) dropwise add titanium ethanolate (IV) (52.3mL in mixture in THF (200mL), 49.84mmol, 1.1 equivalents).At room temperature stirred reaction mixture 18 hours.With water (1000mL) and DCM (300mL) diluted reaction mixture.Filter reaction mixture.Be separated each layer.By DCM (2 × 200mL) aqueous phase extracted.By water (1 × 250mL), the organic phase of the saturated NaCl aqueous solution (1 × 150mL) washing through merging, through MgSO 4dry and vacuum concentration.Namely resistates uses without being further purified.
LC-MS 3：t R=0.98min；[M+H] +=300.0。
The general method of synthesis isoindoline 29
To 1-(the chloro-phenyl of 2-allyloxy-5-) the fluoro-2-of-5-(2-methyl-propan-2-sulfinyl)-2; 3-dihydro-1H-isoindole (230mg; 0.56mmol, 1.0 equivalents) add 4M HCl dioxane solution (2mL) in solution in MeOH (10mL).At room temperature stir the mixture 2 hours.Vacuum concentration reaction mixture.Chloroformic acid benzyl ester (0.10mL, 0.68mmol, 1.2 equivalents) is added in solution in DCM (10mL) to resistates and DIPEA (0.30mL, 1.69mmol, 3.0 equivalents).At room temperature stir the mixture 4 hours.With 1M aqueous citric acid solution (10mL) diluted reaction mixture.Be separated each layer.By DCM (2 × 10mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 10mL) washing through merging, through MgSO 4dry and vacuum concentration.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration, obtain required isoindoline.
The isoindoline 29 prepared as initial substance with corresponding isoindoline derivative 28 according to method mentioned above is enumerated in following table 48.
Table 48
Synthesis (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (C22H24NO3Cl, MW=385.89)
To (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-2-(2-methyl-propan-2-sulfinyl)-2; 3-dihydro-1H-isoindole (10.77g; 27.6mmol, 1.0 equivalents) add 4MHCl dioxane solution (40.0mL) in solution in MeOH (300mL).At room temperature stir the mixture 2 hours.Vacuum concentration reaction mixture.Tert-Butyl dicarbonate (7.23g, 33.1mmol, 1.2 equivalents) is added in solution in DCM (300mL) to resistates and DIPEA (14.5mL, 82.9mmol, 3.0 equivalents).At room temperature stir the mixture 4 hours.With 1M aqueous citric acid solution (100mL) diluted reaction mixture.Be separated each layer.By DCM (2 × 100mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 100mL) washing through merging, through MgSO 4dry and vacuum concentration.By flashmaster (heptane is to heptane+20%AcOEt for tubing string: 340g, flow velocity: 90mL/min) Purification, produce the required product in white foam.
LC-MS 3：t R=1.04min；[M+H] +=386.1。
The general method of synthesis isoindoline 30.
At N 2under at room temperature stir (±)-1-(the chloro-phenyl of 2-allyloxy-5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (10.35g, 26.8mmol, 1.00 equivalents), 1,3-dimethyl barbituric acid (8.38g, 53.6mmol, 2.00 equivalents) and wantonly (triphenylphosphine) palladium (0) (1.55g, 1.34mmol, 0.05 equivalent) mixture in MeOH (300mL) 5 hours.Mixture is allocated between AcOEt (250ml) and water (250ml).Be separated each layer and by AcOEt (2 × 100mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 250mL) washing through merging, through MgSO 4dry and vacuum concentration.By flashmaster (heptane is to heptane+50%AcOEt for tubing string: 340g, flow velocity: 90mL/min) Purification, obtain required phenol 30.
The isoindoline 30 prepared as initial substance with corresponding isoindoline derivative 29 according to method mentioned above is enumerated in following table 49.
Table 49
The general synthesis of the isoindoline of structure 10
To (±)-1-(5-chlorine-2-hydroxyl-phenyl)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (7.47g, 21.6mmol, 1.0 equivalents) and Anhydrous potassium carbonate (4.48g, 32.4mmol, 1.5 equivalents) add ethyl bromoacetate (2.63mL, 23.8mmol, 1.1 equivalents) in mixture in acetone (400mL).At room temperature stir the mixture 18 hours.By in reaction mixture impouring water (150mL).Mixture is extracted with AcOEt (2 × 200mL).Through MgSO 4dry organic phase through merging and vacuum concentration.By flash master (heptane is to heptane+50%EtOAc for tubing string: 340g, flow velocity: 90mL/min) Purification, produce the title product in yellow oily.
The isoindoline of the structure 10 prepared as initial substance with corresponding isoindoline derivative 30 according to method mentioned above is enumerated in following table 50.
Table 50
Synthesis [2-(2-acryl-2,3-dihydro-1H-isoindole-1-base) the chloro-phenoxy group of-4-]-ethyl acetate (enantiomer 1) (C21H20NO4Cl, MW=385.85)
To (S)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (2.16g, 5.0mmol, 1.0 equivalents) add 4M HCl dioxane solution (25mL) in ice cold solution in DCM (100mL).At room temperature stir gained solution 18 hours.Vacuum concentration reaction mixture.To resistates and NEt 3acrylate chloride (0.45mL, 5.5mmol, 1.1 equivalents) is added in (3.48mL, 25mmol, 5.0 equivalents) solution in DCM (100mL).At room temperature stir gained solution 2 hours.Vacuum concentration reaction mixture.By flash master (heptane+20%AcOEt is to heptane+70%AcOEt for tubing string: 100g, flow velocity: 45mL/min) Purification, obtain title compound.
LC-MS 3：t R=0.92min；[M+H] +=385.9。
Follow same program; but with 1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1; 3-DIHYDRO-ISOINDOL-2-t-butyl formate (enantiomer 2) is initiator; preparation [2-(2-acryl-2,3-dihydro-1H-isoindole-1-base) the chloro-phenoxy group of-4-]-ethyl acetate (enantiomer 2).
LC-MS 3：t R=0.92min；[M+H] +=385.9。
Synthesis (S)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate (C26H24NO5Cl, MW=465.93)
To (S)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (86mg, 0.2mmol, 1.00 equivalents) add 4M HCl dioxane solution (5mL) in ice cold solution in DCM (5mL).At room temperature stir gained solution 18 hours.Vacuum concentration reaction mixture.To resistates and NEt 3chloroformic acid benzyl ester (30 μ L, 0.21mmol, 1.05 equivalents) is added in (0.14mL, 1.0mmol, 5.00 equivalents) solution in DCM (5mL).At room temperature stir gained solution 18 hours.Vacuum concentration reaction mixture.By preparation HPLC (tubing string: Atlantis, 18mm × 50mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration.
LC-MS 3：t R=1.03min；[M+H] +=465.9。
Follow same program, but with (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate is initiator, preparation (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate.
LC-MS 3：t R=1.03min；[M+H] +=466.9。
Synthesis (±)-[the chloro-2-of 4-(2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-ethyl acetate hydrochloride (C18H18NO3Cl, MW=331.10)
To (±)-1-(the chloro-2-ethoxycarbonylmethoxy-phenyl of 5-)-1,3-DIHYDRO-ISOINDOL-2-t-butyl formate (2.26g, 5.23mmol, 1.0 equivalents) add 4M HCl dioxane solution (25mL) in ice cold solution in EtOH (100mL).At room temperature stir gained solution 18 hours.Vacuum concentration reaction mixture.With cold methyl tertiary butyl ether (50mL) wet-milling resistates, filter and rinse with cold methyl tertiary butyl ether (20mL), obtaining the required salt in white solid.
LC-MS 3：t R=0.70min；[M+H] +=332.2。
Synthesis (±)-[the chloro-2-of 4-(fluoro-2, the 3-dihydro-1H-isoindole-1-bases of 5-)-phenoxy group]-ethyl acetate hydrochloride (C18H17NO3ClF, MW=349.09)
To (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-5-fluoro-1,3-DIHYDRO-ISOINDOL-2-benzyl formate (165mg, 0.34mmol, 1.0 equivalents) add containing 33% hydrobromic acetic acid (3.0mL) in solution in AcOH (3.0mL).At room temperature stir the mixture 2 hours.Vacuum concentration reaction mixture.At room temperature in the ethanolic soln (5.0mL) of 1.25M HCl, stir resistates 18 hours.Vacuum concentration reaction mixture, obtains the required salt in colorless oil.
LC-MS 3：t R=0.71min；[M+H] +=350.1。
Synthesis (±)-1-(the fluoro-2-hydroxy-pheny of 5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate (C22H18NO3F, MW 363.39)
Step 1: to the fluoro-Benzaldehyde,2-hydroxy (5.0g of 5-, 35.69mmol, 1.00 equivalents) and salt of wormwood (7.97g, 57.10mmol, 1.60 equivalents) dropwise add bromotoluene (4.54mL in mixture in DMF (60mL), 37.47mmol, 1.05 equivalents).Reaction mixture refluxed 2 hours, is then cooled to room temperature and in impouring 100mL cold water, and extracts with AcOEt.With the 10%NaOH aqueous solution and saturated NaCl solution washing organic extract, through MgSO 4dry and vacuum concentration.By flashmaster (heptane is to heptane+30%AcOEt for tubing string: 100g, flow velocity: 45mL/min) Purification, produce the fluoro-phenyl aldehyde of 2-benzyloxy-5-in yellow oily.
Step 2: at N 2the lower 2-iodo-benzoic acid methyl esters (1.0g to cooling at-78 DEG C, THF (1:1) (about 14% in the THF) (554mg of chloride containing isopropyl-magnesium-lithium chloride mixture is dropwise added in solution 3.82mmol) in THF (20mL), 3.82mmol, 1.0 equivalents).Stir the mixture at-78 DEG C 1 hour and at room temperature stir 1 hour again.==> grignard solution A
The fluoro-phenyl aldehyde of 2-benzyloxy-5-(879mg, 3.82mmol, the 1.0 equivalents) solution in THF (10mL) is dropwise added in the grignard solution A at being cooled to-78 DEG C.Stir the mixture at-78 DEG C 1 hour and at room temperature stir 18 hours again.Use 1M NH 4the Cl aqueous solution (50mL) and the careful cancellation reaction of AcOEt (100mL).Via diatomite filtration gained suspension and by water and AcOEt flush cake.Be separated each layer and by AcOEt (2 × 150mL) aqueous phase extracted.By the organic phase of the saturated NaCl aqueous solution (1 × 100mL) washing through merging, through MgSO 4dry and vacuum concentration.By flash master (tubing string: 100g, flow velocity: 45mL/min, heptane is to heptane+45%AcOEt) (±)-3-(2-benzyloxy-5-fluoro-the phenyl)-3H-isobenzofuran-1-ketone of Purification generation in white solid.
Step 3: to lithium aluminium hydride (170mg, 4.49mmol, 1.5 equivalents) ice-cold in THF (30mL) and dropwise adding containing (±)-3-(the fluoro-phenyl of 2-benzyloxy-5-)-3H-isobenzofuran-1-ketone (1.0g in the suspension stirred, 2.99mmol, 1.0 equivalents) THF (20mL).Stir the mixture at 0 DEG C 30 minutes and at room temperature stir 1 hour again.Again mixture is cooled to 0 DEG C and by dropwise iPrOH (15mL) and the 2M NaOH aqueous solution (6mL) Careful hydrolysis.THF flush cake is used via diatomite filtration gained suspension.Vacuum concentrated filtrate.Resistates is diluted with the 2M HCl aqueous solution (150mL) and DCM (150mL).Be separated each layer.By DCM (2 × 50mL) aqueous phase extracted.By water (1 × 150mL), the organic phase of the saturated NaCl aqueous solution (1 × 50mL) washing through merging, through MgSO 4dry and vacuum concentration, obtains (±)-(the fluoro-phenyl of 2-benzyloxy-5-)-(2-methylol-phenyl)-methyl alcohol in colorless oil.
Step 4: to (±)-(the fluoro-phenyl of 2-benzyloxy-5-)-(2-methylol-phenyl)-methyl alcohol (500mg, 1.48mmol, 1.00 equivalents) and DMAP (9mg, 0.07mmol, 0.05 equivalent) dropwise add NEt in ice cold solution in DCM (30mL) 3(0.82mL, 5.91mmol, 4.00 equivalents) and methane sulfonyl chloride (0.24mL, 3.10mmol, 2.10 equivalents).Stir the mixture at 0 DEG C 1 hour and at room temperature stir 2 hours again.Use H 2o (50mL) and DCM (50mL) diluted reaction mixture.Be separated each layer.By DCM (2 × 50mL) aqueous phase extracted.By water (1 × 150mL), the organic phase of the saturated NaCl aqueous solution (1 × 50mL) washing through merging, through MgSO 4dry and vacuum concentration, obtains (±)-methanesulfonic 2-[(the fluoro-phenyl of 2-benzyloxy-5-)-methane sulfonyl oxygen base-methyl]-benzyl ester.
Step 5: to (±)-methanesulfonic 2-[(the fluoro-phenyl of 2-benzyloxy-5-)-methane sulfonyl oxygen base-methyl]-benzyl ester (650mg; 1.31mmol; 1.0 equivalents) sequentially add benzene methanamine (0.19mL in solution in DMF (15mL); 1.71mmol; 1.3 equivalents) and DIPEA (0.69mL; 3.94mmol, 3.0 equivalents).Heated mixt 2 days at 70 DEG C.Reaction mixture is made to be cooled to room temperature and vacuum concentration.Filtration residue, then by preparation HPLC (tubing string: Water X-Bridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) purifying and vacuum concentration, obtain (±)-2-benzyl-1-(the fluoro-phenyl of 2-benzyloxy-5-)-2,3-dihydro-1H-isoindole.
Step 6: at N 2lower to (±)-2-benzyl-1-(the fluoro-phenyl of 2-benzyloxy-5-)-2,3-dihydro-1H-isoindole (181mg, 0.44mmol, 1.0 equivalents) add palladium/activated carbon (10 % by weight, 60mg) in solution in EtOH (20mL).Flask is vacuumized and uses H 2backfill (3 times).At room temperature at H 2black suspension is stirred 18 hours under atmosphere.Via diatomite filtration suspension, rinse diatomite with EtOH.Vacuum concentrated filtrate.Filtration residue, then by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain (±)-2-(2,3-dihydro-1H-isoindole-1-base) the fluoro-phenol of-4-.
Step 7: to (±)-2-(2,3-dihydro-1H-isoindole-1-base) the fluoro-phenol (13mg of-4-, 0.055mmol, 1.00 equivalents) and DIPEA (37 μ L, 0.218mmol, 4.00 equivalents) dropwise add chloroformic acid benzyl ester (8 μ L, 0.057mmol, 1.05 equivalents) in ice cold solution in DCM (2mL).When the addition is complete, cooling bath is removed and at room temperature stirred solution 3 hours.React with 1M aqueous citric acid solution (5mL) cancellation.Be separated each layer.By DCM (3 × 2mL) aqueous phase extracted.Through MgSO 4dry organic phase through merging and vacuum concentration.By preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) Purification and vacuum concentration, obtain (±)-1-(the fluoro-2-hydroxy-pheny of 5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate.
LC-MS 3：t R=0.92min；[M+H] +=364.1。
Synthesis (±)-1-(the chloro-2-Cyanomethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H21N2O3Cl, MW=432.91)
By (±)-1-(5-chlorine-2-hydroxyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (1.9g, 5.00mmol, 1.00 equivalents) and chloromethyl cyanide (0.34mL, 5.19mmol, 1.04 equivalents) mixture in DMSO (1.5mL) is added in the suspension of salt of wormwood (980mg, 7.09mmol, 1.42 equivalents) in DMSO (1.5mL) (heat release).Heated mixt to 80 DEG C and stirring 1 hour under Bi Wendu.By in reaction mixture impouring ice.After ice-out, filtering mixt and use water flush cake.High vacuum dry gained yellow jelly.Namely product uses without being further purified.
LC-MS 3：t R=1.00min；[M+H] +=433.1。
Synthesis (S)-1-(the chloro-2-hydrazinocarbonylmethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H24N3O4Cl, MW=465.94)
To (S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (165mg, 0.36mmol, 1.0 equivalents) sequentially add TBTU (138mg in solution in DMF (0.9mL), 0.43mmol, 1.2 equivalents) and DIPEA (0.19mL, 1.08mmol, 3.0 equivalents).At room temperature stir gained reaction mixture 15 minutes.Then at 0 DEG C, add the solution of 1M hydrazine in anhydrous THF (1.99mL, 1.99mmol, 5.6 equivalents) (heat release).At room temperature stir gained mixture 18 hours.Use DCM diluted reaction mixture, then use saturated NaHCO 3solution washing.With DCM aqueous phase extracted once.Through MgSO 4the dry organic phase through merging, filters and vacuum concentration.By preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) Purification and evaporation, obtain the required product in brown foam.
LC-MS 3：t R=0.92min；[M+H] +=466.3。
Synthesis (±)-1-[the chloro-2-of 5-(N-hydroxy formamidine ylmethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (C25H24N3O4Cl, MW=465.94)
To (±)-1-(the chloro-2-Cyanomethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (866mg, 2.0mmol, 1.0 equivalents) sequentially add water (6mL), hydroxylamine hydrochloride (542mg in solution in EtOH (25mL), 7.6mmol, 3.8 equivalents) and salt of wormwood (485mg, 3.5mmol, 1.8 equivalents).Heated mixt was to backflow maintenance 1 hour.Mixture is made to be cooled to room temperature and vacuum removes solvent.Resistates is allocated between water and DCM.Be separated each layer and with DCM aqueous layer extracted (3 times).Through MgSO 4the dry organic layer through merging, filters and vacuum concentration.Resistates to be dissolved in DMF (5mL) again and by preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, alkaline condition) purifying and evaporation, to obtain the title product in white foam.
LC-MS 3：t R=0.84min；[M+H] +=466.2。
Synthesis (±)-5-[the chloro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxymethyl]-isoxazol-3-ols (C19H17N2O3Cl, MW=356.81)
Step 1: to (3-benzyloxy-isoxazole-5-base)-methyl alcohol (500mg, 2.44mmol, 1.00 equivalents, as people such as R.Riess, prepare described in Eur.J.Org.Chem.1998,473-479) sequentially add NEt in ice cold solution in DCM (5.1mL) 3(0.39mL, 2.8mmol, 1.15 equivalents), DMAP (3mg, 0.02mmol, 0.01 equivalent) and methylsulfonyl chloride (0.22mL, 2.8mmol, 1.15 equivalents).Stirred reaction mixture 2.5 hours at 0 DEG C, then vacuum concentration obtains methanesulfonic 3-benzyloxy-isoxazole-5-base methyl esters.Product is without being further purified namely for next step.
Step 2: to (±)-1-(5-chlorine-2-hydroxyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (159mg, 0.4mmol, 1 equivalent) add salt of wormwood (166mg in solution in MeCN (0.8mL), 1.2mmol, 3 equivalents) and methanesulfonic 3-benzyloxy-isoxazole-5-base methyl esters (113mg, 0.4mmol, 1 equivalent).Stirred reaction mixture 18 hours at 80 DEG C.Use MeCN/H 2o 1:1 (1mL) dilution mixture thing and by preparation HPLC (tubing string: Atlantis, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and vacuum concentration, obtain (±)-1-[2-(3-benzyloxy-isoxazole-5-base methoxyl group) the chloro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates.
Step 3: at room temperature stir (±)-1-[2-(3-benzyloxy-isoxazole-5-base methoxyl group) the chloro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate (70mg, 0.12mmol, 1 equivalent) in containing the solution in 33% hydrobromic acetic acid (0.64mL) 1.5 hours.Vacuum removes solvent.Resistates to be dissolved in again in MeCN/MeOH and by preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) purifying and evaporation (genevac), obtain (±)-5-[chloro-2-of 4-(1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxymethyl]-isoxazol-3-ols.
LC-MS 3：t R=0.66min；[M+H] +=357.2。
The general method of synthesis of phenyl butyric acid 45.
At N 2lower to bromobenzene 43 (5.00mmol, 1.00 equivalents) and four (triphenylphosphine) palladium (0) (289mg, 0.25mmol, 0.05 equivalent) add the THF solution (20mL of 0.5N bromination 4-oxyethyl group-4-oxo butyl zinc in solution in THF (10mL), 10.00mmol, 2.00 equivalents).Stir the mixture at 50 DEG C 18 hours.Mixture is made to be cooled to room temperature and vacuum concentration.Required phenylpropionic acid ester is produced by flashmaster (heptane is to heptane+AcOEt for tubing string: 100g, flow velocity: 45mL/min) Purification.The 1M NaOH aqueous solution (4mL) is added in the solution of this ester in THF (8mL) and MeOH (2mL).At 50 DEG C, stir yellow solution 18 hours, then vacuum removes organic solvent.With 2NHCl aqueous solution careful acidification gained water layer.Mixture is extracted with DCM (3 × 20mL).Through MgSO 4dry organic phase through merging and vacuum concentration, obtain required acid.Namely product uses without being further purified.
The phenylbutyric acid 45 prepared as initial substance with corresponding bromobenzene 43 according to method mentioned above is enumerated in following table 51.
Table 51
The general method of synthesis Cyclopropanecarboxylacid acid derivative 49.
Step 1:2-chloro-cinnamic acid (1.84g, 10.0mmol, 1.0 equivalents) and N, O-dimethyl hydroxylamine hydrochloride (995mg, 10.0mmol, 1.0 equivalents) solution 4-(dimethylamino) pyridine (4.89g in DMF (60mL), 40.0mmol, 4.0 equivalent) and N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (2.88g, 15.0mmol, 1.5 equivalents) process and at room temperature stir gained solution 62 hours.With AcOEt (1L) diluted reaction mixture.With the 1N HCl aqueous solution (3 × 400mL), saturated NaHCO 3the aqueous solution (3 × 400mL), the saturated NaCl aqueous solution (1 × 400mL) wash diluted solution, through MgSO 4dry and vacuum concentration, obtains the required acid amides in faint yellow oily.Namely product uses without being further purified.
LC-MS 3：t R=0.80min；[M+H] +=226.2。
Step 2: at N 2the lower trimethylammonium sulfoxonium (2.20g being maintained at room temperature through 10 points of clockwise water-baths, 10.0mmol, 2.0 equivalents) add sodium hydride (60% dispersion liquid in mineral oil, 400mg by part in solution in DMSO (10mL), 10.0mmol, 2.0 equivalents).At room temperature stir gained mixture 1 hour.Add (E)-3-(the chloro-phenyl of 2-)-N-methoxy-. N-methyl-acrylamide (1.14g, 5.0mmol, 1.0 equivalents) solution in DMSO (5mL) and at room temperature stirred reaction mixture 19 hours.By saturated for reaction mixture impouring NH 4to extract with DCM (3 × 50mL) in the Cl aqueous solution (50mL).By the organic phase of the saturated NaCl aqueous solution (1 × 50mL) washing through merging, through MgSO 4dry and vacuum concentration.By CC (SiO 2, Hept/AcOEt) and Purification, obtain the required cyclopropyl in colorless oil.
LC-MS 2：t R=0.75min；[M+H] +=240.2。
Step 3: to (±)-(instead)-2-(the chloro-phenyl of 2-)-cyclopropane-carboxylic acid methoxy-methyl-amide (1.00g, 4.20mmol, 1.0 equivalents) in Et 2the trimethyl carbinol (2.54g, 22.66mmol, 5.4 equivalents) and H is added in solution in O (30mL) 2o (0.15mL).At room temperature stir the mixture 18 hours.Vacuum concentration reaction mixture.Resistates is dissolved in H 2in O and with dense HCl careful acidification solution.Mixture is extracted with DCM (3 × 20mL).Through MgSO 4the dry organic phase through merging, filters and vacuum concentration, and obtain the required acid in colorless oil, it is solidified on standing.Namely resistates uses without being further purified.
To enumerate according to the corresponding α of method mentioned above in following table 52a and table 52b, the cyclopropyl acid 49 that beta-unsaturated acid 46 is prepared as initial substance.
Table 52a
Table 52b
Synthesis { the chloro-2-of 4-[(S)-2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-ethyl acetate (C29H28NO4Cl, MW=490.00)
Amine (the chloro-2-1 of (S)-4-, 2,3,4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate (456mg, 1.31mmol, 1.0 equivalents) and (±)-(instead)-2-cyclo-propane-1-formic acid (219mg, 1.31mmol, 1.0 equivalent) solution DMAP (240mg in DMF (8mL), 1.97mmol, 1.5 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (377mg, 1.97mmol, 1.5 equivalents) process and at room temperature stir gained solution 18 hours.With AcOEt (150mL) diluted reaction mixture.With the 1N HCl aqueous solution (3 × 50mL), saturated NaHCO 3the aqueous solution (3 × 50mL), the saturated NaCl aqueous solution (1 × 50mL) wash diluted solution, through MgSO 4drying, filters and vacuum concentration, obtains required acid amides.
LC-MS 3：t R=1.04min；[M+H] +=490.0。
The general method of cyclopropane-carboxylic acid 49 and (the chloro-2-1 of (S)-4-, 2,3,4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate hydrochloride acid amides coupling and saponification reaction subsequently
Amine (the chloro-2-1 of (S)-4-, 2, 3, 4-tetrahydro-isoquinoline-1-base-phenoxy group)-ethyl acetate hydrochloride (210mg, 0.50mmol, 1.0 equivalents) and (±)-(instead)-2-(2-trifluoromethyl-phenyl)-cyclopropane-carboxylic acid (116mg, 0.50mmol, 1.0 equivalent) solution DMAP (490mg in DMF (3mL), 4.00mmol, 8.0 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (288mg, 1.50mmol, 3.0 equivalents) process and at room temperature stir gained solution 96 hours.With AcOEt (50mL) diluted reaction mixture.With the 1N HCl aqueous solution (3 × 20mL), saturated NaHCO 3the aqueous solution (3 × 20mL), the saturated NaCl aqueous solution (1 × 20mL) wash diluted solution, through MgSO 4drying, filters and vacuum concentration.The 1M NaOH aqueous solution (0.64mL) is added in the solution of resistates in THF (2mL).At room temperature stirred solution 18 hours.Vacuum concentration reaction mixture.Dilute with water resistates and washing with AcOEt.With 2N HCl acidified aqueous solution aqueous phase.Mixture is extracted with DCM.Through MgSO 4the dry organic phase through merging, filters and vacuum concentration, obtains required acid.
The example of formula (I) compound prepared as initial substance according to method respective acids mentioned above is enumerated in following table 53.
Table 53
Synthesis (±)-{ 2-[2-(the bromo-ethanoyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate (C21H21NO4BrF, MW=450.30)
At N 2lower to (±)-[fluoro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (2.0g, 5.2mmol, 1.0 equivalents) add N-ethyl diisopropylamine (2.7mL, 15.6mmol, 3.0 equivalents) in ice cold solution in DCM (13mL).Dropwise add bromoacetyl bromide (0.5mL, 5.7mmol, the 1.1 equivalents) solution in DCM (5mL).Remove cooling bath and at room temperature stir brown solution 2 hours.With AcOEt (170mL) diluting soln, use saturated NaHCO 3the aqueous solution (1 × 90mL), with the washing of the saturated NaCl aqueous solution (1 × 90mL), through MgSO 4dry and vacuum concentration.The title compound in brown oil is produced by flash master (heptane is to heptane+AcOEt for tubing string: 100g, flow velocity: 35mL/min) Purification.
LC-MS 2：t R=0.86min；[M+H] +=449.6。
Synthesis (±)-{ 2-[2-(2-benzyloxycarbonyl amino-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate (C29H29N2O6F, MW=520.56)
N-carbobenzoxyglycine (1.07g, 5.00mmol, 1.0 equivalents) and (±)-[fluoro-2-(1 of 4-, 2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-ethyl acetate hydrochloride (1.93g, 5.00mmol, 1.0 equivalents) solution 4-(dimethylamino) pyridine (2.44g in DMF (30mL), 20.00mmol, 4.0 equivalents) and N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride (1.44g, 7.50mmol, 1.5 equivalents) process and at room temperature stir gained solution 18 hours.With AcOEt (500mL) diluted reaction mixture.With the 1N HCl aqueous solution (3 × 200mL), saturated NaHCO 3the aqueous solution (3 × 200mL), the saturated NaCl aqueous solution (1 × 200mL) wash diluted solution, through MgSO 4drying, and vacuum concentration.The title product in white foam is produced by flash master (heptane is to heptane+AcOEt for tubing string: 100g, flow velocity: 35mL/min) purification of crude product.
LC-MS 2：t R=0.92min；[M+H] +=521.1。
Synthesis (±)-{ 2-[2-(2-Amino-acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate hydrochloride (C21H24N2O4ClF, MW=422.88)
At N 2lower to (±)-{ 2-[2-(2-benzyloxycarbonyl amino-ethanoyl)-1; 2; 3; 4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-ethyl acetate (1.81g; 3.48mmol; 1.0 equivalents) add palladium/activated carbon (10% weight, 181mg) in solution in EtOH (17mL).Flask is carefully vacuumized and uses H 2backfill (3 times).At room temperature at H 2black suspension is stirred 18 hours under atmosphere.Through diatomite filtration black suspension.Diatomite is rinsed with EtOH.Vacuum concentrated filtrate.Resistates is dissolved in 4M HCl dioxane solution (20mL).At room temperature stir gained solution 30 minutes, then vacuum concentration.Crude salt to be dissolved in EtOH and vacuum concentration (3 times), to obtain the title salt in weak yellow foam shape.
LC-MS 2：t R=0.64min；[M+H] +=387.2。
The general method of synthesis indazole 9.
At room temperature in the solution of 5 points of chloro-2'-fluoro acetophenones of clockwise 4'-(0.7mL, 5mmol, 1 equivalent) in DME (5mL), add single hydrazine hydrate (5mL, 5mmol, 1 equivalent).Then reaction mixture refluxed 24 hours in sealing microwave vial.Mixture is made to be cooled to room temperature and vacuum removes solvent.Add water.Filter gained suspension and by preparation HPLC (tubing string: Waters XBridge, 30mm × 75mm, 10 μm, UV/MS, acidic conditions) pure solid and evaporation, obtain the required indazole in white solid.
The indazole 9 prepared as initial substance with corresponding 2'-fluoro acetophenone according to method mentioned above is enumerated in following table 54.
Table 54
Chiral separation
The enantiomer or diastereomer that are separated by the chiral stationary phase of preparation HPLC is enumerated in table 55.The condition be separated is:
Method CS1: tubing string DaiCel ChiralPak IB (20mm × 250mm, 5 μm), eluent A90% heptane and eluent B 10%EtOH, flow velocity: 16mL/min.
Method CS2: tubing string DaiCel ChiralPak IB (20mm × 250mm, 5 μm), eluent A95% heptane and eluent B 15%EtOH, flow velocity: 16mL/min.
Method CS3: tubing string DaiCel ChiralPak OD (20mm × 250mm, 10 μm), eluent A95% heptane and eluent B 5%EtOH, flow velocity: 16mL/min.
Method CS4: tubing string DaiCel ChiralPak AD-H (20mm × 250mm, 5 μm), eluent A 60% heptane and eluent B 40%EtOH, flow velocity: 16mL/min.
Method CS5: tubing string DaiCel ChiralPak AD-H (20mm × 250mm, 5 μm), eluent A 95% heptane and eluent B 5%EtOH, flow velocity: 16mL/min.
Method CS6: tubing string DaiCel ChiralPak OD-H (20mm × 250mm, 5 μm), eluent A 85% heptane and eluent B 15%EtOH, flow velocity: 16mL/min.
Method CS7: tubing string DaiCel ChiralPak AD-H (20mm × 250mm, 5 μm), eluent A 85% heptane and eluent B 15%EtOH, flow velocity: 16mL/min.
Method CS8: tubing string DaiCel ChiralPak AD-H (20mm × 250mm, 5 μm), eluent A 80% heptane and eluent B 20%EtOH, flow velocity: 16mL/min.
Method CS9: tubing string DaiCel ChiralPak AD-H (30 × 250mm, 5 μm), eluent A90% heptane and eluent B 10%EtOH, flow velocity: 34mL/min.
Table 55
Measure three-dimensional chemical configuration
The absolute configuration that X-ray analysis assesses tetrahydroisoquinoline is carried out by the compound 50 obtained according to the program as described in flow process 20.Racemize phenol 51, through mapping pure toluene sulphonate 52 (obtained when buying alcohol with toluene sulfonyl chloride process is corresponding under NEt3 and triethylamine hydrochloride exist) alkylation, wherein supposes that alkylated reaction carries out via upset.By chiral preparative HPLC (condition: tubing string DaicelChiralPak OD (20mm × 250mm, 10 μm), eluent A 95% heptane and eluent B 5%EtOH, flow velocity: 16mL/min) mixture 53 of separating obtained diastereomer, obtain two kinds of enantiomer-pure esters, its saponification becomes acid 50 and acid 54.Combine in calibrating at CRTH2, acid 50 has more activity; It is by the solution of slow evaporation in DCM and crystallization, and for X-ray analysis.
Flow process 20. measures the absolute stereochemical configuration of tetrahydroisoquinoline.
Follow asymmetric synthesis that the people such as Charette (JACS 1998,120,11943-11952) develop to assess the absolute configuration of phenycyclopropyl ring.Make the esterification of commercially available styracin 55 and reduction, obtain homoallylic alcohol 56, it is Cyclopropanated to there is asymmetric Xi Meng-Smith (Simmons-Smith) under existing in its ligand 57 at stoichiometric quantity.Then be oxidized gained alcohol, obtain required acid 58.Obtain the acid 58 of enantiomerism excessive 88%, and judge (assignment) by comparing to confirm (S, S) with disclosed data people such as (, J.Med.Chem.2009,52,1885-1902) S.J.Cho., there is saponification reaction afterwards and obtain finalization compound 60 in acid 58 and the coupling of amine 59 acid amides under EDC exists as alkali as activator and DMAP.Obtain the compound 60 of enantiomerism excessive 96%, and it has antagonistic activity, IC through measuring in radioligand displacement calibrating (hereinafter described) 50=215nM.Comparatively speaking, by the chiral stationary phase of preparation HPLC (condition: tubing string Daicel ChiralPak IB (20mm × 250mm, 5 μm), eluent A90% heptane and eluent B 10%EtOH, flow velocity: 16mL/min) be separated non-enantiomer mixture 61, obtain two kinds of enantiomer-pure esters.The saponification under the 1M NaOH aqueous solution exists of gained two kinds of esters, obtains two kinds of optical purity acid 62 and 60; Thus obtained sour 60 have the identical residence time with the acid obtained by intermediate 58 and 59, and it is shown as active poor isomer (62:IC in radioligand displacement calibrating 50=1.39nM; 60:IC 50=1000nM).The three-dimensional chemical configuration containing other examples of phenyl-cyclopropyl-carbonyl moiety obtained by chirality chromatography carries out similar judgement, means and supposes that having more active isomer has (R, R)-configuration in two stereogenic centres of cyclopropyl rings.
Flow process 21. measures the absolute stereochemical configuration of phenycyclopropyl part.
Bioassay:
The preparation of hCRTH2 receptor membrane and radioligand displacement calibrating:
First, rubber policeman is used will to recombinate HEK293-hCRTH 2cell is peeled off to 5ml buffer A/culture plate (buffer A: 5mM Tris, 1mM MgCl in culture plate 2-6H 2o, pH=7.4).Then cell to be transferred in centrifuge tube and under 400g centrifugal 5 minutes.Cell is made to assemble grain settling flux freezing each pipe in same buffer and at-80 DEG C.By cell thawing and by use polytron clarifixator carry out homogenizing (30 seconds) produce membrane-bound fragment.Then under 3000g centrifugal membrane-bound fragment 20 minutes and settling flux in damping fluid C (damping fluid C:75mM Tris, 25mM MgCl 2, 250mM sucrose, pH 7.4) in.At the aliquots containig of membrane-bound fragment is stored in-20 DEG C.
Perform with the final calibrating volume of 250 μ l and combine calibrating.First, 25 μ l had previously been used binding buffer liquid (binding buffer liquid: 50mM Tris-Base, 100mM NaCl, 1mM EDTA, 0.1%BSA (without proteolytic enzyme), 0.01%NaN 3, 10mM MnCl 2, pH 7.0) and the test compounds of diluting is placed in each hole.After adding 75 μ l binding buffer liquid, by 50 μ l radioligand 3h-PGD 2(2.5nM (every hole 220.000dpm), from ANAWA ART0662) is added in each hole.By interpolation 100 μ l CRTH 2the initial combination calibrating of membrane-bound fragment, reaches the ultimate density of every hole 20 μ g.For non-specific binding, by PGD 2be added in reaction mixture and reach ultimate density 10mM.At room temperature cultivate this calibrating mixture 90 minutes, then filter via at the 0.5% poly-GF/C strainer 96 hole culture plate soaked in advance 3 hours of stretching in ethyliminum (PEI).With the washed filter opening of ice-cold binding buffer liquid three times.Then, 40 μ l Microscint-40 (Packard) to be added in each hole and with Topcount (Packard) quantitatively residual activity.
The antagonistic activity of exemplary compounds is presented in following table.
Radioligand displacement calibrating-human serum albumin (HSA):
Under human serum albumin (HSA) exists, perform radioligand displacement calibrating as mentioned above, wherein carry out following amendment.Binding buffer liquid-HSA: binding buffer liquid+from the 0.5%Sigma albumin (substitute 0.1%BSA) of serum human A1887.The test compounds that the previous binding buffer liquid-HSA of 25 μ l volumes dilutes is placed in each hole.After adding 75 μ l binding buffer liquid-HSA, by 50 μ l 3h-PGD 2(2.5nM (every hole 220.000dpm), from ANAWA ART0662) is added in each hole.All the other schemes are with consistent as mentioned above.
Reference:
Shimizu T,Yamashita A,Hayaishi O.Specific binding of prostaglandin D2 torat brain synaptic membranes.J.Biol.Chem.1982。257th volume: 13570-13575.
Fortini A,Modesti PA,Abbate R,Gensini GF,Neri Serneri GG.Heparin doesnot interfere with prostacyclin and prostaglandin D2 binding to platelets.Thromb.Res.1985。40th volume: 319-328.
Sawyer N,Cauchon E,Chateauneuf A,Cruz RP,Nicholson DW,Metters KM,O'Neill GP,Gervais FG.Molecular pharmacology of the human PGD2 receptorCRTH2.Br.J.of Pharmacol.2002。137th volume: 1163-1172.
Examining and determine addicted to Yihong blood cell deformation of human plasma
After signature Informed Consent Form, according to the scheme ratified through Basel, SUI Ethics Committee (ethics committee ofBasel, Switzerland) by taken by venipuncture blood sample.Use Polymorphprep tMmethod (Axis-Shield) is separated polymorphic nucleus white cell (containing addicted to Yihong blood cell, basophilia white cell and neutrophils).In brief, anticoagulated whole blood layer is added in Polymorphprep gradient (density is 1.113g/ml), and under 500g centrifugal 30min.Collect polymorphonuclear cell part and consume red blood corpuscle by hypotonic physiological saline water dissolution.
Make polymorphonuclear cell with 5 × 10 6individual cells/ml settling flux is in examining and determine damping fluid (containing Ca 2+/ Mg 2+1 × PBS, be supplemented with 0.1%BSA, 10mM HEPES and 10mM glucose, pH 7.4) in, and at room temperature to dye 1 hour with anti-CD49d-APC (APC=allophycocyanin).The test compounds 10 minutes (using thrombin inhibitors anti-freezing) of the various concentration of pre-incubation in human plasma.Then, human plasma is added in polymorphonuclear cell the final calibrating volume reaching 50%, wherein polymorphonuclear cell is 4 × 10 6individual cells/ml.Cultivate after 10 minutes at 37 DEG C, be the PGD of 100nM by interpolation ultimate density at 37 DEG C 2activation polymorphonuclear cell 5 minutes.Activation is stopped by interpolation 0.5ml trioxymethylene (1%).
Immediately by FACSCanto flow cytometer (BD Biosciences) analytic sample after fixing with trioxymethylene, and by the forward scatter (FSC) of target cell and lateral scattering (SSC) characteristic differentiation target cell.Differentiated by anti-CD49d-APC signal and characteristic lateral scattering (SSC) overview thereof addicted to Yihong blood cell.The per-cent of the cell indicating the deformation reaction addicted to the activation of Yihong blood cell to increase with forward scatter comes quantitatively.
Intracellular Ca2+ moves calibrating (FLIPR):
Standard mammalian cell culture condition (37 DEG C, in 5%CO 2moistening atmosphere in) under, by stablizing the cell (HEK-293) of performance hCRTH2 acceptor in single insertion display carriers pcDNA5 (Invitrogen) in being supplemented with 10% foetal calf serum (Bioconcept under the huge viral promotors of cell controls, Switzerland) grow in DMEM (low dextrose content, Gibco) substratum and converge.Use dissociates damping fluid (containing the PBS of 0.02%EDTA, Gibco) cell is peeled off 1 minute from culture dish, and by under at room temperature 200g in calibrating damping fluid (Han Keshi BSS (Hank's the BSS) (HBSS of equal portions, and DMEM (low dextrose content Bioconcept), without phenol red, Gibco)) within centrifugal 5 minutes, collect.In calibrating damping fluid, cultivation 45 minutes (37 DEG C and 5%CO under 1 μM of Fluo-4 and 0.04%Pluronic F-127 (all deriving from Molecular Probes) and 20mM HEPES (Gibco) exists 2) after, with calibrating buffer solution cell and settling flux in calibrating damping fluid, be then inoculated in 384 hole FLIPR with every hole 66 μ l containing 50,000 cell and examine and determine on culture plate (Greiner), and by centrifugal sedimentation.
With the stock solution of 10mM concentration preparation test compounds in DMSO, and with examining and determine the concentration of buffer serial-dilution to inhibitor quantitative response Curves need.PGD 2(Biomol, PlymouthMeeting, PA) is as agonist.
According to standard specification operation FLIPR Tetra instrument (Molecular Devices) of manufacturers, add 4 μ l 10mM test compounds and be dissolved in solution in DMSO, and before the experiments with the dilution of calibrating damping fluid to obtain required ultimate density.Then 10 μ l 80nM PGDs are added 2(Biomol, Plymouth Meeting, PA) solution in the calibrating damping fluid being supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), obtains the ultimate density being respectively 10nM and 0.1%.At λ ex=488nm and λ emthe fluorescence that under=540nm, monitoring is added before and after test compounds changes.Export after deducting baseline value and add PGD 2afterwards higher than the emission peak of basal level.(do not add PGD deducting baseline value 2) after, correct numerical value relative to high-level contrast (not adding test compounds).Data fitting is become the single-point dose response curve of equation (A+ ((B-A)/(1+ ((C/x) ^D)))) and calculates IC by service routine XLlfit 3.0 (IDBS) 50value.

Claims (16)

1. formula (I) compound:
(I)
Wherein
X represents-NH-,-O-or a key;
Y represents (C 1-C 4) alkane two base;
Z represents O or S;
N represents 0 or 1;
R 1represent
(C 4-C 6) alkyl;
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group, heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group, the Heteroarylthio be optionally substituted or-NR 8r 9monosubstituted; Wherein
Term " aryl be optionally substituted " refers to phenyl or naphthyl, described phenyl or naphthyl is unsubstituted independently, through monosubstituted, to replace through two or through three replacements, wherein substituting group is independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) alkyl sulphonyl, cyano group, phenyl and 5-methyl-tetrazole-1-base;
Term " heteroaryl be optionally substituted " refers to containing 1,2,3 or 4 heteroatomic 5 to 10 yuan of monocycle independently selected from oxygen, nitrogen and sulphur or Bicyclic aryl rings, wherein this heteroaryl be unsubstituted independently, through monosubstituted, to replace through two or through three replacements, wherein substituting group is independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, trifluoromethyl, cyano group and phenyl, wherein this phenyl is unsubstituted or monosubstituted or two replacements through methyl;
Term " heterocyclic radical be optionally substituted " refers to the saturated monocyclic moeity of heteroatomic 5 to 7 ring memberses being selected from nitrogen, oxygen and sulphur containing 1 or 2, should be appreciated that heterocyclic radical not containing 2 sulphur atoms, the sulphur atom of heterocyclic radical can be oxidised form, namely in sulfoxide or alkylsulfonyl form, and heterocyclic radical can optionally and phenyl ring ring, wherein heterocyclic radical is unsubstituted, independently through monosubstituted or through two replacements, wherein substituting group is independently selected from the group be made up of oxo base and phenyl;
Term " aryloxy be optionally substituted " refers to phenyl-O-group, this phenyl be unsubstituted, through monosubstituted, to replace through two or through three replacements, wherein substituting group is independently selected from by the following group formed: halogen and (C 1-C 4) alkyl;
Term " the heteroaryl oxygen base be optionally substituted " refers to heteroaryl-O-group, wherein this heteroaryl refers to containing 1,2,3 or 4 heteroatomic 5 to 10 yuan of monocycle independently selected from oxygen, nitrogen and sulphur or Bicyclic aryl rings, wherein this heteroaryl oxygen base be unsubstituted independently, through monosubstituted, to replace through two or through three replacements, wherein substituting group is independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, 2-Hydroxy-ethoxy, cyano group ,-C (O) NH 2and trifluoromethyl;
Term " the aryl be optionally substituted-(C 1-C 2) alkoxyl group " and refer to one of them hydrogen atom phenyl displacement (C 1-C 2) alkoxyl group, described phenyl to be unsubstituted or through monosubstituted, and wherein substituting group is independently selected from by the following group formed: halogen, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group;
Term " the heteroaryl be optionally substituted-(C 1-C 2) alkoxyl group " and refer to one of them hydrogen atom heteroaryl displacement (C 1-C 2) alkoxyl group, wherein term " heteroaryl " refers to containing 1 or 2 heteroatomic 5 or 6 yuan of bicyclic heteroaryl independently selected from oxygen, nitrogen and sulphur, and wherein this heteroaryl is independently through (C 1-C 4) alkyl is monosubstituted; And
Term " Heteroarylthio be optionally substituted " refers to triazolyl sulfenyl, and wherein triazolyl sulfenyl is monosubstituted through phenyl;
(C 2-C 4) thiazolinyl, its aryl through being optionally substituted is monosubstituted; Wherein term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted or through monosubstituted, and wherein substituting group is independently selected from by the following group formed: halogen and (C 1-C 4) alkyl;
(C 2-C 4) alkynyl, its aryl through being optionally substituted is monosubstituted; Wherein term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted;
(C 3-C 6) cycloalkyl, it is through (C 1-C 4) alkyl is monosubstituted or two replace, through (C 1-C 4) alkoxyl group is monosubstituted, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted; Wherein
Term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted, through monosubstituted or through two replacements, and wherein substituting group is independently selected from by the following group formed: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and (C 1-C 4) fluoroalkyl; And
Term " heteroaryl be optionally substituted " refers to thiazolyl, and wherein this thiazolyl is through (C 1-C 4) alkyl two replaces;
The aryl be optionally substituted; Wherein term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted or through monosubstituted, and wherein substituting group is independently selected from by the following group formed: halogen and (C 1-C 4) alkoxyl group; Or
Tetralyl or chromenyl;
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, (C 1-C 4) alkyl sulphonyl, benzenesulfonyl or (C 1-C 4) alkyl sulfonyl amino;
R 3represent hydrogen, (C 1-C 4) alkoxy or halogen;
R 4represent hydrogen, (C 1-C 4) alkoxyl group, halogen, (C 1-C 4) alkyl sulphonyl, the aryl be optionally substituted or the heteroaryl be optionally substituted; Wherein
Term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted or monosubstituted through halogen; And
Term " heteroaryl be optionally substituted " refers to pyrimidyl, and wherein this pyrimidyl is unsubstituted;
R 5represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, halogen, cyano group ,-CONH 2, the optionally aryl, the heteroaryl be optionally the substituted, (C that are substituted 1-C 4) alkyl sulphonyl, benzenesulfonyl or dimethylamino-alkylsulfonyl; Wherein
Term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted or monosubstituted through halogen; And
Term " heteroaryl be optionally substituted " refers to containing 1,2 or 3 heteroatomic 5 or 6 yuan of bicyclic heteroaryl independently selected from oxygen, nitrogen and sulphur, and wherein this heteroaryl is unsubstituted or monosubstituted through sulfydryl independently; And
R 6represent hydrogen or halogen; Or
R 5and R 6form methylene-dioxy together;
R 7represent hydrogen or methyl;
R 8represent hydrogen or methyl;
R 9represent the aryl, the aryl sulfonyl be optionally substituted or the heteroarylsulfonyl be optionally substituted that are optionally substituted; Wherein
Term " aryl be optionally substituted " refers to phenyl, and described phenyl is unsubstituted;
Term " aryl sulfonyl be optionally substituted " refers to aryl-S (O) 2-group, wherein this aryl refers to phenyl, and it is the rest part being connected to molecule via sulphur atom, and described phenyl is unsubstituted, through monosubstituted or through two replacements, and wherein substituting group is independently selected from by the following group formed: halogen; And
Term " heteroarylsulfonyl be optionally substituted " refers to that isoxazolyl alkylsulfonyl ， isoxazolyl alkylsulfonyl is through two replacements, and wherein substituting group is independently selected from by the following group formed: (C 1-C 4) alkyl; And
R 10represent-C (O) OH ,-C (O) NH-CN ,-C (O) NH-OH ,-C (O) NH-S (O) 2cF 3or the heteroaryl be optionally substituted; Wherein term " heteroaryl be optionally substituted " refers to containing 1,2,3 or 4 heteroatomic 5 yuan or 6 yuan of bicyclic heteroaryl independently selected from oxygen, nitrogen and sulphur, and heteroaryl is unsubstituted or monosubstituted through hydroxyl independently;
If its restricted condition represents-NH-or a key for X, then R 1aryl not for being optionally substituted;
Or the salt of this compound.
2. compound as claimed in claim 1, wherein
X represents-O-or a key;
Y represents methylene radical;
Z represents O;
N represents 0 or 1;
R 1represent
(C 1-C 2) alkyl, its aryl, the heteroaryl be optionally substituted or aryl-(C be optionally substituted through being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, its aryl through being optionally substituted is monosubstituted;
R 2represent hydrogen, trifluoromethyl or fluorine;
R 3represent hydrogen or fluorine;
R 4represent hydrogen;
R 5represent halogen or cyano group;
R 6represent hydrogen;
R 7represent hydrogen; And
R 10represent-C (O) OH;
Or the salt of this compound.
3. compound as claimed in claim 1, wherein
X represents-O-;
Or the salt of this compound.
4. compound as claimed in claim 1, wherein
X represents a key;
Or the salt of this compound.
5. the compound according to any one of Claims 1-4, wherein
Z represents O;
Or the salt of this compound.
6. the compound according to any one of claim 1 or 3 or 4, wherein
R 1represent
(C 1-C 4) alkyl, it is through (C 3-C 6) cycloalkyl, the aryl be optionally substituted, the heteroaryl be optionally substituted, the heterocyclic radical be optionally substituted, the aryloxy be optionally substituted, the heteroaryl oxygen base be optionally substituted, aryl-(C of being optionally substituted 1-C 2) alkoxyl group or heteroaryl-(C of being optionally substituted 1-C 2) alkoxyl group is monosubstituted; Or
Cyclopropyl, it is through (C 1-C 4) alkyl monosubstituted or two replace, monosubstituted or through being optionally substituted the heteroaryl of the aryl through being optionally substituted is monosubstituted;
Or the salt of this compound.
7. the compound according to any one of claim 1 or 3 or 4, wherein
R 2represent hydrogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl or halogen;
Or the salt of this compound.
8. the compound according to any one of claim 1 or 3 or 4, wherein
R 4represent hydrogen or halogen;
Or the salt of this compound.
9. the compound according to any one of Claims 1-4, wherein
R 5represent halogen or cyano group;
Or the salt of this compound.
10. the compound according to any one of Claims 1-4, wherein
R 7represent hydrogen;
Or the salt of this compound.
11. compounds according to any one of Claims 1-4, wherein
R 10represent-C (O) OH;
Or the salt of this compound.
12. compounds as claimed in claim 1, it is selected from by the following group formed:
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((S)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(2-Carboxvmethoxv-5-methylphenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the bromo-2-carboxymethoxy-phenyl of 5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
The bromo-1-of 7-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-4,5-difluorophenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
The bromo-1-of 5-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((R)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(5-bromo-2-carboxymethoxy-phenyl)-6,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-6,7-bis-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-trifluoromethyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-((R)-1-carboxyl-oxyethyl group)-5-cvano-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5,6-bis-;
1-(2-Carboxvmethoxv-5-dimethylsulfamoyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5-;
1-(2-Carboxvmethoxv-5-trifluoromethyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-isopropyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(6-Carboxvmethoxv-benzo [1,3] dioxole-5-base)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-methoxyl group-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(2-Carboxvmethoxv-5-cvano-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-[2-((R)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
(S)-1-[2-((S)-1-carboxyl-oxyethyl group) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
{ the fluoro-2-of 4-[(S)-2-((trans)-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(2-Carboxvmethoxv-5-cvano-phenyl)-5-;
1-(2-Carboxvmethoxv-3,5-difluorophenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methoxyl group-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-methoxyl group-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Chloro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of the bromo-1-of 5-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,7-bis-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(2-Carboxvmethoxv-5-cvano-phenyl)-5,7-bis-;
2-[2-(2-benzo [d] isoxazole-3-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-methyl-3-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-naphthalene-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-quinoline-7-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-quinoline-6-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxine-6-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(2-{2-[3-(1-Ethyl-2-Methyl-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(2,6-Dichloro-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[3-(the fluoro-phenoxy group of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[the fluoro-2-of 4-(2-{2-[4-(5-methyl-tetrazole-1-base)-phenyl]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-methYl-thiazol-4-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ 2-[2-(2-benzo [b] thiene-3-yl--ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(3-benzothiazole-2-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(2-biphenyl-4-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(2-indoles-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-1H-benzimidazolyl-2 radicals-Ji-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ 2-[2-(2-1,3-DIHYDRO-ISOINDOL-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
(the fluoro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(2-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-cyclopropyl-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2H-chromene-3-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-Methoxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-phenyl of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(2-indoles-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(2-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(1,2,3,4-tetrahydrochysene-naphthalene-2-carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzoglyoxaline-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the chloro-phenoxy group of-4-}-acetic acid;
{ the chloro-2-of 4-[2-(2-3,4-dihydro-2H-quinoline-1-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-indazole-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(3-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-is trans-[2-(the chloro-phenyl of 2-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } and-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-phenyl-1H-imidazoles-2-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4-oxo-2-Phenyl-thiazol alkane-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[the chloro-2-of 4-(2-{3-[3-(2,3-Dimethvl-phenyl)-3H-imidazol-4 yl]-propionyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-is to tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-phenoxy group of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(2-trifluoromethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-1H-indol-3-yl of 5-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(6-Mehtoxy-Benzofuran-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 4-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between 3-tolyloxy-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-phenoxy group of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-1H-indol-3-yl of 5-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(4-p-methylphenyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzo of 5-[b] thiene-3-yl-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-1H-indoles-2-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methyl-benzo [d] isoxazole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-benzo [d] isoxazole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 4-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzyloxy-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the chloro-phenoxy group of-4-}-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 3-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(2,3-Dichloro-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between 4-tolyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(4-o-tolyl-butyryl radicals)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 3-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the chloro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(3-methoxyl group-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[4-(the fluoro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of 2-(2-benzyloxy-ethanoyl)-5-] the chloro-phenoxy group of-4-}-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-5-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-phenyl-propioloyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(3-phenyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
[the fluoro-2-of 4-(2-phenyl acetyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the fluoro-2-of 4-[2-(2-phenoxy-acetyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(2-benzyloxy-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(4-phenyl-butyryl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[3-(2-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(3-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[3-(4-methoxyl group-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 3-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[3-(the chloro-phenyl of 4-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
{ the fluoro-2-of 4-[2-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-naphthalene-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(2-oxy-o-cresyl-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[2-(1-Methyl-1H-indole-3-base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(the chloro-phenoxy group of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[3-(the fluoro-phenyl of 2-)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-(2-indane-2-base-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[(E)-3-(the fluoro-phenyl of 2-)-acryl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the fluoro-2-of 4-[2-((E)-3-o-tolyl-acryl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(5-phenyl-pentanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the fluoro-2-of 4-[2-(3-phenoxy group-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[3-(4-Methanesulfonyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ 2-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
{ the fluoro-2-of 4-[2-(3-oxy-o-cresyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-phenoxy group of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[4-(2-methoxyl group-phenyl)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the chloro-2-{2-of 4-[(trans)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-((trans)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[(trans)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the chloro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2,4-Dichloro-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2-methoxyl group-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-phenyl-3H-[1,2,3] triazole-4-yl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(3-phenyl-3H-[1,2,3] triazole-4-yl sulfenyl)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-6-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,2-dimethyl-propyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-butyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-phenyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-phenyl formate;
The chloro-phenyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-tetryl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-ethyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methoxy-phenyl ester;
(S) the chloro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of 2-)-ethyl ester;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of 2-)-ethyl ester;
The chloro-phenyl ester of 1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
Fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the chloro-phenyl of the 2-)-ethyl esters of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-7-ethanesulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-Methanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(5-benzenesulfonyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-ethanesulfonyl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methane sulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-ethanesulfonyl-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
5-benzenesulfonyl-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-pyrimidine-5-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(the fluoro-biphenyl of 4-Carboxvmethoxv-4'--3-base)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(2-{2-[2-(the chloro-benzyloxy of 3-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[2-(the chloro-benzyloxy of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(3-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(4-methyl-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(3-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(4-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(1-methyl isophthalic acid H-pyrazole-3-yl methoxyl group)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(2-Methoxy-benzyloxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
[2-(2-benzyl carbamyl-1,2,3,4-tetrahydro-isoquinoline-1-base) the fluoro-phenoxy group of-4-]-acetic acid;
[the fluoro-2-of 4-(2-phenethyl-carbamoyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the fluoro-2-of 4-[2-(2-methyoxy-benzyl carbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2-methyoxy-benzyl carbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ 2-[2-(the chloro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases] the fluoro-phenoxy group of-4-}-acetic acid;
(2-{2-[2-(the chloro-phenyl of 2-)-ethyl carbamyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
{ 2-[2-(2-BENZENESUFONYLAMINO-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-1-base] the fluoro-phenoxy group of-4-}-acetic acid;
(2-{2-[2-(3,5-dimethyl-isoxazole-4-sulfuryl amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-BENZENESUFONYLAMINO of 3-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-{2-of 4-[2-(the fluoro-BENZENESUFONYLAMINO of 2-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(2-{2-[2-(3,4-Difluoro-benzenesulfonyl is amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
(2-{2-[2-(N-benzenesulfonyl-N-Methyl-amino)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases } the fluoro-phenoxy group of-4-)-acetic acid;
[the fluoro-2-of 4-(2-{2-[N-(the fluoro-benzenesulfonyl of 3-)-N-Methyl-amino]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases)-phenoxy group]-acetic acid;
[2-(2-{2-[N-(3,4-Difluoro-benzenesulfonyl)-N-Methyl-amino]-ethanoyl }-1,2,3,4-tetrahydro-isoquinoline-1-bases) the fluoro-phenoxy group of-4-]-acetic acid;
1-(5-carbamyl-2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-Carboxvmethoxv-5-(5-sulfo--4,5-dihydro-[and 1,2,4] oxadiazole-3-bases)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-4-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-6-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-[2-(3-carboxyl-propoxy-) the fluoro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
{ 4-cyano group-2-[2-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
1-(2-Carboxvmethoxv-5-cvano-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(R)-1-[2-(1-carboxyl-oxyethyl group) the chloro-phenyl of-5-]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
(S)-1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-5-methanesulfonylamino-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-[1,2,3] triazol-1-yl-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
1-(2-Carboxvmethoxv-5-[1,2,3] triazole-2-base-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate; And
{ the chloro-2-of 4-[2-(2-methyoxy-benzyl thiocarbamyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
Or the salt of this compound.
13. compounds as claimed in claim 1, it is selected from by the following group formed:
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
The bromo-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate;
{ the chloro-2-of 4-[(S)-2-((1R, 2R)-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-trifluoromethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-trifluoromethyl-benzyl ester;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-bis-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-dimethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-dimethyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethyl-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4,6-trimethylammoniums-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-6-of dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-bis-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,4-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-dimethoxys-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,6-dimethyl-pyridin-3-yl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-cyano group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-bis-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-2-of dihydro-1H-isoquinoline 99.9-2-formic acid 5-;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3, the 4-chloro-5-of dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-acid cyclohexyl base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-pyrazole-3-yl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid cyclopentyl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-tetryl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-butyl formate;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxy-ethyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid cyclopropyl methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3,5-Dimethyl-pyrazol-1-base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methyl-isoxazole-3-base methyl esters;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1,5-dimethyl-1H-pyrazole-3-yl methyl esters;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-Ji)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3,5-dimethyl-isoxazole-4-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-5-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formate;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of 3-)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,5-dimethyl-2H-pyrazole-3-yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-base)-ethyl ester;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [d] isoxazole-3-base methyl esters;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-the Ji)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3, the 5-dimethyl-isoxazole-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of the 3-)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2, the 5-dimethyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl) of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis--ethyl ester;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-the base)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [d] the isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-carboxylic acid thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(4-methyl-thiazole-5-the Ji)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 5-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methYl-thiazol-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-thiazole-5-Ji methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methYl-thiazol-4-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-isoxazole-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrazine-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-4-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid pyrimidine-5-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-phenylethyl formates of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(the fluoro-phenyl of the 3-)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2, the 5-dimethyl-2H-pyrazole-3-yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(2-ethyl-5-methyl-2H-pyrazole-3-yl) of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6--ethyl ester;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-methyl-3H-imidazol-4 yl methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-(3,5-Dimethyl-pyrazol-1-the base)-ethyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl pyrazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzothiazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid benzoxazole-2-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 1-methyl isophthalic acid H-indazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid indazole-1-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) fluoro-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid benzo [the d] isoxazole-3-base methyl esters of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5,6-bis-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2,3-bis-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(S) the fluoro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
(S)-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-methoxyl group-benzyl ester;
(S) the fluoro-benzyl ester of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
(S) the fluoro-benzyl ester of fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-formic acid 2-of-1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methyl-benzyl ester;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-methoxyl group-benzyl ester;
The fluoro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-;
1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 4-trifluoromethyl-benzyl ester;
The chloro-benzyl ester of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid 3-;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-7-;
1-(2-carboxymethoxy-phenyl)-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formate;
Fluoro-3, the 4-dihydro-1H-isoquinoline 99.9-2-benzyl formates of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-6-;
(the chloro-2-{2-of 4-[3-(the fluoro-3-Methvl-indole of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-methoxyl group-pyrrolo-[2,3-b] pyridine-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4,6-dimethoxy-pyrrolo-[2,3-b] pyridine-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(4,6-dimethoxy-indoles-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-indoles-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indoles of 7--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-pyrrolo-[3,2-b] pyridine-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(4-Methoxv-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indazole of 3--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-Methvl-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-indoles of 6--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 4--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indoles of 6--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(6-Methoxv-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{ of 4-(S)-6-[3-(the fluoro-indazole of 5--1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{ of 4-(S)-6-[3-(3-methyl-indazol-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[3-(the chloro-indazole of 6--1-base)-propionyl] fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of-6-}-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-pyrrolo-of 3-[2,3-b] pyrazine-5-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-phenoxy group of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(quinoline-8-yl oxygen base)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-phenoxy group of 4-)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(trans-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[trans-2-(3-methoxyl group-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(between trans-2-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(trans-2-phenyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[trans-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-phenyl of trans-2-)-cyclopropyl carbonyl]-6-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(trans-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl] fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of-6-}-phenoxy group)-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 6-(3-o-tolyl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the fluoro-2-of the chloro-2-{6-of 4-[4-(the fluoro-phenyl of 2-)-butyryl radicals]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(fluoro-1,2,3, the 4-tetrahydro-isoquinoline-1-base of the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-6-}-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(3-Methvl-indole-1-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-indazole-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-3,4-dihydro-2H-quinoline-1-base-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(2,4-Dimehtyl-phenoxy)-ethanoyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1-Methyl-1H-indole-3-base)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-1H-indol-3-yl-propionyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(2,2-dimethyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the chloro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 3-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
[2-(2-benzyl carbamyl-1,2,3,4-tetrahydro-isoquinoline-1-base) the chloro-phenoxy group of-4-]-acetic acid;
[the chloro-2-of 4-(2-phenethyl-carbamoyl-1,2,3,4-tetrahydro-isoquinoline-1-base)-phenoxy group]-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 4-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 2-)-1,2,3,4-tetrahydro-isoquinoline-1-bases]-phenoxy group }-acetic acid;
1-(the fluoro-phenyl of 2-Carboxvmethoxv-5-)-1,3-DIHYDRO-ISOINDOL-2-benzyl formate;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-5-;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4-;
{ the chloro-2-of 4-[2-is trans-(2-phenyl-cyclopropyl carbonyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(the fluoro-phenoxy group of 4-)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(quinoline-8-yl oxygen base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(5-methoxyl group-1H-indol-3-yl)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(2,6-dimethyl-pyridin-3-yl oxygen base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(1-Methyl-1H-indole-3-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(3-2,3-Dihydro-indole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(3-indazole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[2-(5-methoxyl group-benzo [d] isoxazole-3-base)-ethanoyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-Methvl-indole-1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[2-(the chloro-benzyloxy of 2-)-ethanoyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-phenoxy group of 2-)-propionyl]-2,3-dihydro-1H-isoindole-1-base }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-is trans-[2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-2,3-dihydro-1H-isoindole-1-base } and-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-is trans-[2-(the fluoro-phenyl of 2-)-cyclopropyl carbonyl]-2,3-dihydro-1H-isoindole-1-base } and-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[the fluoro-2-of 5-(3-indazole-1-base-propionyl)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 5--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-3-methyl-indazol of 4--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-3-methyl-indazol of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the chloro-3-methyl-indazol of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(3-methyl-indazol-1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 6--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 4--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{2-of 4-[3-(the fluoro-indazole of 7--1-base)-propionyl]-2,3-dihydro-1H-isoindole-1-bases }-phenoxy group)-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 2-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 3-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
{ the chloro-2-of 4-[2-(the fluoro-benzyl carbamyl of 4-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
[2-(2-benzyl carbamyl-2,3-dihydro-1H-isoindole-1-base) the chloro-phenoxy group of-4-]-acetic acid;
[the chloro-2-of 4-(2-phenethyl-carbamoyl-2,3-dihydro-1H-isoindole-1-base)-phenoxy group]-acetic acid;
{ the chloro-2-of 4-[2-(the chloro-benzyl carbamyl of 2-)-2,3-dihydro-1H-isoindole-1-base]-phenoxy group }-acetic acid;
Chloro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,5-bis-;
Fluoro-1, the 3-DIHYDRO-ISOINDOL-2-benzyl formate of 1-(the chloro-phenyl of 2-Carboxvmethoxv-5-)-4,5-bis-;
{ the chloro-2-of 4-[(S)-2-((1R, 2R)-2-o-tolyl-cyclopropyl carbonyl)-1,2,3,4-tetrahydro-isoquinoline-1-base]-phenoxy group }-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(2-trifluoromethyl-phenyl)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the chloro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 3-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(the chloro-2-{ of 4-(S)-2-[(1R, 2R)-2-(the fluoro-phenyl of 4-)-cyclopropyl carbonyl]-1,2,3,4-tetrahydro-isoquinoline-1-bases }-phenoxy group)-acetic acid;
(S)-1-[the chloro-2-of 5-(2-oxo-2-trifluoromethanesulphonylamino-oxyethyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
(S)-1-[the chloro-2-of 5-(5-oxo-4,5-dihydro-[1,3,4] oxadiazole-2-ylmethoxies)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates; And
1-[the chloro-2-of 5-(3-hydroxyl-isoxazole-5-base methoxyl group)-phenyl]-3,4-dihydro-1H-isoquinoline 99.9-2-benzyl formates;
Or the salt of this compound.
14. 1 kinds of medical compositions, it comprises compound according to any one of claim 1 to 13 or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
The purposes of 15. 1 kinds of compounds according to any one of claim 1 to 13 or its pharmaceutically acceptable salt, it is for the preparation of being selected from by the medicament of the disease of the following group formed in order to prevention and/or treatment: asthma, rhinitis, angioedema, insect venom allergies, drug allergy, allergic sinusitis, allergic nephritis, anaphylaxis conjunctivitis, atopic dermatitis, food anaphylaxis, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease, inflammatory enteropathy, rheumatoid arthritis, Xie Ge-Si Tuosi syndrome, Wei Genashi granuloma, microscopic Polyangiitis is addicted to Yihong blood cell pneumonia, addicted to Yihong blood cell esophagitis, reflux esophagitis, addicted to Yihong blood cell endocarditis, addicted to her erythrocytosis-myalgia syndrome, addicted to Yihong blood cell fascitis, addicted to Yihong blood cell pustule type folliculitis, addicted to Yihong blood cell ulcer, ALH is concurrent addicted to her erythrocytosis, addicted to Yihong blood cell cellulitis, chronic addicted to Yihong blood cell leukemia, DRESS syndrome, Basophilic leukemia and basophilia leukocytosis disease.
16. the purposes of a compound according to any one of claim 1 to 13 or its pharmaceutically acceptable salt, it is for the preparation of being selected from by the medicament of the disease of the following group formed in order to prevention and/or treatment: allergic asthma, addicted to Yihong blood cell asthma, severe asthma, allergic rhinitis, angioedema, insect venom allergies, drug allergy, allergic sinusitis, allergic nephritis, anaphylaxis conjunctivitis, atopic dermatitis, bronchial asthma, food anaphylaxis, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, ulcerative colitis, chronic obstructive pulmonary disease, inflammatory enteropathy, rheumatoid arthritis, Xie Ge-Si Tuosi syndrome, Wei Genashi granuloma, microscopic Polyangiitis, addicted to Yihong blood cell pneumonia, addicted to Yihong blood cell esophagitis, reflux esophagitis, addicted to Yihong blood cell endocarditis, addicted to her erythrocytosis-myalgia syndrome, addicted to Yihong blood cell fascitis, addicted to Yihong blood cell pustule type folliculitis, concurrent addicted to her erythrocytosis, addicted to Yihong blood cell cellulitis, chronic addicted to Yihong blood cell leukemia, DRESS syndrome addicted to Yihong blood cell ulcer, ALH, Basophilic leukemia and basophilia leukocytosis disease.
CN201180030390.1A 2010-07-05 2011-07-04 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators Expired - Fee Related CN102958914B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IB2010053071 2010-07-05
IBPCT/IB2010/053071 2010-07-05
PCT/IB2011/052944 WO2012004722A1 (en) 2010-07-05 2011-07-04 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

Publications (2)

Publication Number Publication Date
CN102958914A CN102958914A (en) 2013-03-06
CN102958914B true CN102958914B (en) 2015-05-27

Family

ID=44645751

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201180030390.1A Expired - Fee Related CN102958914B (en) 2010-07-05 2011-07-04 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators

Country Status (13)

Country Link
US (1) US8575158B2 (en)
EP (1) EP2590944B1 (en)
JP (1) JP5800898B2 (en)
KR (1) KR101920090B1 (en)
CN (1) CN102958914B (en)
AU (1) AU2011275417A1 (en)
BR (1) BR112013000254A2 (en)
CA (1) CA2805452C (en)
ES (1) ES2553871T3 (en)
MX (1) MX2012015082A (en)
RU (1) RU2013104506A (en)
TW (1) TW201201805A (en)
WO (1) WO2012004722A1 (en)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8476297B2 (en) 2007-12-04 2013-07-02 Amgen Inc. TRP-M8 receptor ligands and their use in treatments
KR20140107550A (en) 2011-12-21 2014-09-04 액테리온 파마슈티칼 리미티드 Heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
JP6127135B2 (en) * 2012-07-05 2017-05-10 アクテリオン ファーマシューティカルズ リミテッドＡｃｔｅｌｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ 1-Phenyl substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
EP3382391A1 (en) 2012-10-24 2018-10-03 NYU Winthrop Hospital Non-invasive biomarker to identify subjects at risk of preterm delivery
JP2016532648A (en) * 2013-10-09 2016-10-20 イーライ リリー アンド カンパニー Novel pyridyloxyacetyl tetrahydroisoquinoline compounds useful as NAMPT inhibitors
CN107072970B (en) * 2014-08-29 2021-05-25 得克萨斯州大学***董事会 Novel capsazepine analogs useful in the treatment of cancer and other proliferative diseases
KR20180012858A (en) 2015-06-15 2018-02-06 엔엠디 파마 에이피에스 Compounds for use in the treatment of neuromuscular disorders
MX2020002788A (en) 2017-09-13 2020-09-14 Progenity Inc Preeclampsia biomarkers and related systems and methods.
US11147788B2 (en) 2017-12-14 2021-10-19 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
US11730714B2 (en) 2017-12-14 2023-08-22 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
US10385028B2 (en) 2017-12-14 2019-08-20 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
TWI780281B (en) * 2017-12-14 2022-10-11 丹麥商Ｎｍｄ藥品公司 Compounds for the treatment of neuromuscular disorders
US11591284B2 (en) 2017-12-14 2023-02-28 Nmd Pharma A/S Compounds for the treatment of neuromuscular disorders
EP4070113A4 (en) 2019-12-04 2023-12-20 Biora Therapeutics, Inc. Assessment of preeclampsia using assays for free and dissociated placental growth factor
CN111960999B (en) * 2020-07-20 2021-11-02 暨明医药科技（苏州）有限公司 Synthetic method of tetrabenazine intermediate

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2388540A (en) * 2002-05-17 2003-11-19 Bayer Ag New use of Ramatroban
WO2005087743A1 (en) * 2004-03-12 2005-09-22 Analytecon S.A. Tetrahydroisoquinoline-and tetrahydrobenzazepine derivatives as igf-1r inhibitors
WO2005105727A1 (en) * 2004-05-04 2005-11-10 Novartis Ag Crth2 receptor antagonists
WO2007052023A2 (en) * 2005-11-05 2007-05-10 Astrazeneca Ab Novel compounds

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995035107A1 (en) * 1994-06-20 1995-12-28 Smithkline Beecham Corporation Endothelin receptor antagonists
US5929106A (en) * 1997-10-27 1999-07-27 Smithkline Beecham Corporation Endothelin receptor antagonists
JP4279561B2 (en) 2001-05-23 2009-06-17 メルク フロスト カナダ リミテツド Dihydropyrrolo [1,2-a] indole and tetrahydropyrido [1,2-a] -indole derivatives as prostaglandin D2 receptor antagonists
EP2423190A1 (en) 2002-05-16 2012-02-29 Shionogi&Co., Ltd. Compounds Exhibiting PGD 2 Receptor Antagonism
AU2003231513A1 (en) 2002-05-16 2003-12-02 Shionogi And Co., Ltd. Pgd2 receptor antagonist
BR0315041A (en) 2002-10-04 2005-08-16 Millennium Pharm Inc Methods for inhibiting crth2 in an individual requiring crth2 inhibition; compound; and pharmaceutical composition
ES2263015T3 (en) 2002-10-21 2006-12-01 Warner-Lambert Company Llc TETRAHYDROQUINOLINE DERIVATIVES AS AN ANTHOGONIST OF CRTH2
EP1413306A1 (en) 2002-10-21 2004-04-28 Warner-Lambert Company LLC Tetrahydroquinoline derivatives as CRTH2 antagonists
AU2003297398B2 (en) 2002-12-20 2009-09-24 Amgen Inc. Asthma and allergic inflammation modulators
EP1435356A1 (en) 2003-01-06 2004-07-07 Warner-Lambert Company LLC Quinoline derivatives as CRTH2 antagonists
SE0301010D0 (en) 2003-04-07 2003-04-07 Astrazeneca Ab Novel compounds
SE0301009D0 (en) 2003-04-07 2003-04-07 Astrazeneca Ab Novel compounds
ATE316077T1 (en) 2003-04-25 2006-02-15 Actimis Pharmaceuticals Inc PYRIMIDINE ACID DERIVATIVES SUITABLE FOR THE TREATMENT OF CRTH2-RELATED DISEASES
SA04250253B1 (en) 2003-08-21 2009-11-10 استرازينيكا ايه بي Substiuted phenoxacetic as pharmaceutced compunds for treating respiratory diseases such as asthma and copd
JP4996257B2 (en) 2004-01-31 2012-08-08 アクチミス ファーマシューティカルズ インコーポレーテッド Imidazo [1,2-c] pyrimidinylacetic acid derivatives
TW200538127A (en) 2004-04-07 2005-12-01 Millennium Pharm Inc PGD2 receptor antagonists for the treatment of inflammatory diseases
BRPI0510043A (en) 2004-04-20 2007-10-16 Pfizer method of treating neuropathic pain using crth2 receptor antagonist
WO2005115382A1 (en) 2004-05-29 2005-12-08 7Tm Pharma A/S Crth2 receptor ligands for medicinal uses
GB0415320D0 (en) 2004-07-08 2004-08-11 Astrazeneca Ab Novel compounds
GB0418830D0 (en) 2004-08-24 2004-09-22 Astrazeneca Ab Novel compounds
GB0422057D0 (en) 2004-10-05 2004-11-03 Astrazeneca Ab Novel compounds
HN2005000795A (en) 2004-10-15 2010-08-19 Aventis Pharma Inc PYRIMIDINS AS ANTAGONISTS OF PROSTAGLANDINA D2 RECEPTOR
WO2006056752A1 (en) 2004-11-23 2006-06-01 Astrazeneca Ab Phenoxyacetic acid derivatives useful for treating respiratory diseases
CN101146776A (en) 2005-02-24 2008-03-19 米伦纽姆医药公司 PGD2 receptor antagonists for the treatment of inflammatory diseases
GB0510584D0 (en) 2005-05-24 2005-06-29 Novartis Ag Organic compounds
GB0510585D0 (en) 2005-05-24 2005-06-29 Novartis Ag Organic compounds
JP5072594B2 (en) 2005-07-22 2012-11-14 塩野義製薬株式会社 Indole derivatives having PGD2 receptor antagonist activity
US7842692B2 (en) 2005-07-22 2010-11-30 Shionogi & Co., Ltd. Azaindole derivative having PGD2 receptor antagonistic activity
US8143285B2 (en) 2005-09-06 2012-03-27 Shionogi & Co., Ltd. Indolecarboxylic acid derivative having PGD2 receptor antagonistic activity
BRPI0616574A2 (en) 2005-09-27 2009-11-24 Shionogi & Co sulfonamide derivative having pgd2 receptor antagonistic activity
DK1928457T3 (en) 2005-09-30 2013-02-04 Pulmagen Therapeutics Asthma Ltd QUINOLINES AND THEIR THERAPEUTIC USE
TW200745003A (en) 2005-10-06 2007-12-16 Astrazeneca Ab Novel compounds
WO2007039736A1 (en) 2005-10-06 2007-04-12 Astrazeneca Ab Novel compounds
WO2007062678A1 (en) 2005-11-29 2007-06-07 7Tm Pharma A/S Phenoxyacetic acid derivatives as crth2 receptor ligands
GB0524428D0 (en) 2005-11-30 2006-01-11 7Tm Pharma As Medicinal use of receptor ligands
AR060403A1 (en) 2006-04-12 2008-06-11 Sanofi Aventis AMINO COMPOUNDS- PYRIMIDINE 2.6- SUBSTITUTES -4- MONOSUSTITUTES AS ANTAGONISTS OF PROSTAGLANDINA D2 RECEIVER
CN101490001A (en) 2006-06-09 2009-07-22 Icos股份有限公司 Substituted phenyl acetic acids as DP-2 antagonists
JP2009539880A (en) 2006-06-09 2009-11-19 アイコス コーポレイション Substituted phenylacetic acid as a DP-2 antagonist
GB0611781D0 (en) 2006-06-14 2006-07-26 Argenta Discovery Ltd 2-Oxo-2H-Chromene Compounds
CN101636386A (en) 2006-12-14 2010-01-27 安斯泰来制药有限公司 Polycyclic acid compounds useful as CRTH2 antagonists and antiallergic agents
CA2680636A1 (en) 2007-03-29 2008-10-09 Nicholas Charles Ray Quinoline derivatives as crth2 receptor ligands
ATE532780T1 (en) * 2007-04-04 2011-11-15 Pulmagen Therapeutics Asthma Ltd QUINOLINES AND THEIR THERAPEUTIC USE
UA100983C2 (en) 2007-07-05 2013-02-25 Астразенека Аб Biphenyloxypropanoic acid as crth2 modulator and intermediates
WO2009061730A2 (en) 2007-11-05 2009-05-14 Array Biopharma Inc. 4-heteroaryl-substituted phenoxyphenylacetic acid
GB0722055D0 (en) 2007-11-09 2007-12-19 Argenta Discovery Ltd Compounds
US20110136877A1 (en) 2008-01-07 2011-06-09 Ligand Pharmaceuticals Inc. 2-phenyl phenoxyacetic acids useful for treating inflammatory disorders
NZ587709A (en) 2008-02-01 2012-06-29 Panmira Pharmaceuticals Llc N,n-disubstituted aminoalkylbiphenyl antagonists of prostaglandin d2 receptors
US8242145B2 (en) 2008-02-14 2012-08-14 Panmira Pharmaceuticals, Llc Cyclic diaryl ether compounds as antagonists of prostaglandin D2 receptors
US8497381B2 (en) 2008-02-25 2013-07-30 Panmira Pharmaceuticals, Llc Antagonists of prostaglandin D2 receptors
US8426449B2 (en) 2008-04-02 2013-04-23 Panmira Pharmaceuticals, Llc Aminoalkylphenyl antagonists of prostaglandin D2 receptors
EP2307362A4 (en) 2008-07-03 2012-05-09 Panmira Pharmaceuticals Llc Antagonists of prostaglandin d2 receptors
EP2321268A2 (en) 2008-08-15 2011-05-18 F. Hoffmann-La Roche AG Bi-aryl aminotetralines
EP2321267A2 (en) 2008-08-15 2011-05-18 F. Hoffmann-La Roche AG Monoaryl aminotetralines
CN102066317A (en) 2008-08-15 2011-05-18 霍夫曼-拉罗奇有限公司 Substituted aminotetralines
US8524748B2 (en) 2008-10-08 2013-09-03 Panmira Pharmaceuticals, Llc Heteroalkyl biphenyl antagonists of prostaglandin D2 receptors
PL2346819T3 (en) 2008-11-17 2013-09-30 Hoffmann La Roche Naphthylacetic acids
US20120129820A1 (en) 2009-02-09 2012-05-24 Boehringer Ingelheim International Gmbh New pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
AU2010212970A1 (en) 2009-02-12 2011-08-18 Merck Serono S.A. Phenoxy acetic acid derivatives
WO2010102154A2 (en) 2009-03-05 2010-09-10 Ligand Pharmaceuticals Incorporated Biaryl oxyacetic acid compounds
WO2011002814A2 (en) 2009-06-30 2011-01-06 Ligand Pharmaceuticals Inc. Biaryl oxyacetic acid compounds
KR20120046762A (en) 2009-07-31 2012-05-10 판미라 파마슈티칼스, 엘엘씨 Dermal formulations of dp2 receptor antagonists
EP2461809A4 (en) 2009-07-31 2013-06-19 Panmira Pharmaceuticals Llc Ophthalmic pharmaceutical compositions of dp2 receptor antagonists
SG178252A1 (en) 2009-08-05 2012-03-29 Panmira Pharmaceuticals Llc Dp2 antagonist and uses thereof
WO2011055270A1 (en) 2009-11-04 2011-05-12 Wyeth Llc Indole based receptor crth2 antagonists
ES2635030T3 (en) 2010-12-23 2017-10-02 Merck Sharp & Dohme Corp. Quinoxalines and aza-quinoxalines as modulators of the CRTH2 receptor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2388540A (en) * 2002-05-17 2003-11-19 Bayer Ag New use of Ramatroban
WO2005087743A1 (en) * 2004-03-12 2005-09-22 Analytecon S.A. Tetrahydroisoquinoline-and tetrahydrobenzazepine derivatives as igf-1r inhibitors
WO2005105727A1 (en) * 2004-05-04 2005-11-10 Novartis Ag Crth2 receptor antagonists
WO2007052023A2 (en) * 2005-11-05 2007-05-10 Astrazeneca Ab Novel compounds

Also Published As

Publication number Publication date
WO2012004722A1 (en) 2012-01-12
JP5800898B2 (en) 2015-10-28
ES2553871T3 (en) 2015-12-14
CN102958914A (en) 2013-03-06
EP2590944B1 (en) 2015-09-30
KR101920090B1 (en) 2018-11-19
CA2805452C (en) 2018-07-31
RU2013104506A (en) 2014-08-10
US8575158B2 (en) 2013-11-05
TW201201805A (en) 2012-01-16
KR20130089245A (en) 2013-08-09
EP2590944A1 (en) 2013-05-15
JP2013529678A (en) 2013-07-22
MX2012015082A (en) 2013-02-21
US20130109685A1 (en) 2013-05-02
CA2805452A1 (en) 2012-01-12
BR112013000254A2 (en) 2016-05-24
AU2011275417A1 (en) 2013-02-21

Similar Documents

Publication Publication Date Title
CN102958914B (en) 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin D2 receptor modulators
TWI787620B (en) Benzisoxazole sulfonamide derivatives
CN103958479B (en) Pyrazolo qualone derivative, its preparation and its therapeutical uses
KR101605061B1 (en) Aryl substituted carboxamide derivatives as calcium or sodium channel blockers
CN103998042B (en) The activity of PI3K or the application of the inhibitor of function
TW201738228A (en) Inhibitors of RET
CN108341777A (en) Compound of isobioquin group and its application
CN107690281A (en) Cystic fibrosis transmembrance regulator conditioning agent
CN107771176A (en) The inhibitor of human immunodeficiency virus replication
CN101119969A (en) Use of aryl- and heteroaryl-substituted tetrahydroisoquinolines to block reuptake of norepinephrine, dopamine, and serotonin
CN101094848A (en) Organic compounds
JP2009539881A (en) Substituted phenylacetic acid as a DP-2 antagonist
KR20110063447A (en) Pyrazolopyrimidines and their use for the treatment of cns disorders
CN102171196A (en) Oxazole derivatives useful as inhibitors of FAAH
CN111867585A (en) Oxadiazole transient receptor potential channel inhibitors
KR20110091550A (en) Novel pyrazole-3-carboxamide derivative having 5-ht2b receptor antagonist activity
TW201625528A (en) N-alkylaryl-5-oxyaryl-octahydro-cyclopenta[C]pyrrole negative allosteric modulators of NR2B
KR20180030913A (en) Aryl-substituted bicyclic heteroaryl compounds
CN113226462A (en) Heteroaromatic compounds as VANIN inhibitors
KR20010033609A (en) Tetrahydrobenzindole derivatives
CN104011021B (en) Hete rocyclic derivatives and the purposes as prostaglandin D 2 receptor conditioning agent thereof
WO2002053568A1 (en) Cholesterol biosynthesis inhibitors containing as the active ingredient tricyclic spiro compounds
CN115551864A (en) Substituted tricyclic amides, analogs thereof, and methods of using the same
CN104428305A (en) 1-phenyl-substituted heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20171019

Address after: Swiss A Skei Weil

Patentee after: Aidu West Pharmaceutical Co. Ltd.

Address before: Swiss A Skei Weil

Patentee before: Actelion Pharmaceuticals Ltd.

TR01 Transfer of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150527

Termination date: 20210704

CF01 Termination of patent right due to non-payment of annual fee